Effects of the environment on respiratory tract health in children and adults and observed sex differences.
Abstract
Accumulating evidence indicates that exposure to air pollution is associated with increased mortality from respiratory disease. Exposure to ambient pollutants, such as ozone, particulate matter, sulfur dioxide, nitrogen dioxide, and other agents has been associated with decrease in lung function and immunity, and with increased rates of hospitalization for lung disease, including pneumonia. Furthermore, sex differences in frequency and severity of pulmonary disease and infection have been reported, suggesting a role of sex hormones in mediating these differences. Pneumonia, which is commonly caused by bacterial infection and subsequent lung inflammation leading to hospitalization and death, occurs at different rates in men and women. In this context, male and female hormones can have direct effects on the immunity system by binding to receptors in immune cells, and these responses can be modulated by environmental exposures. This chapter summarizes clinical, animal, and epidemiological studies linking exposure to air pollution and pneumonia in both males and females. Understanding sex-specific mechanisms in pneumonia pathogenesis and environmental responses can help in the development of more effective therapeutics and treatment options to reduce negative health outcomes in men and women.
Keywords
- sex differences
- ozone
- particulate matter
- air pollution
- sex hormones
- community-acquired pneumonia
- environmental exposures
1. Introduction
Regulation of the lung inflammatory response is critical to the successful resolution of pneumonia. Exposure to air pollutants has been linked to negative lung health outcomes, and both male and female sex hormones have been shown to control the lung immune response [1, 2]. This chapter combines evidence of three areas: pneumonia infection, air pollution, and hormonal control of sex-specific immune responses. We will discuss common pathogens responsible for pneumonia and associations with environmental exposures, and lessons learned from animal models of infection and exposure to various air pollutants. Together, this information could help better explain the differences observed in susceptibility to pneumonia between men and women, and help in the development of better treatment options for male and female patients.
2. Pneumonia in the clinic: classification, comorbidities, and pathogenesis
2.1. Classification
Pneumonia is classified according to the patient population affected as: (a) community-acquired pneumonia (CAP), (b) hospital-acquired pneumonia (HAP), (c) ventilator-associated pneumonia (VAP), and (d) nursing home-associated pneumonia (NHAP) [3]. Of these classifications, CAP is the most frequently found, predominantly affecting young children because of the immaturity of their immune system, and older adults due to their immunosenescence and comorbidities of aging [4].
Community-acquired pneumonia is a common infection that affects the lower respiratory tract and it is acquired outside of the hospital or within 48 h of admission, and it is primarily associated with the presence of a new infiltrate on the chest radiograph [2, 3]. Community-acquired pneumonia is often caused by pathogens of the not multidrug-resistant type (MDR), which is an important distinction from the other types of pneumonia. However, some patients with recent antibiotic therapy could also present infection with MDR organisms [3, 5]. Furthermore, most patients are presented with common clinical symptoms, such as fever, cough, pleuritic chest pain, and breathing difficulty, although these symptoms can be absent in elderly patients. Elderly patients, on the other hand, can also have delirium, abdominal pain, or acute cardiac disorders as part of their clinical presentation [4].
2.2. Incidence and risk factors
Despite newer antimicrobial therapy and treatment guidelines, CAP continues to be a significant problem associated with high mortality, morbidity, and cost. In the United States alone, CAP affects approximately 5.6 million patients annually, and it is the sixth cause of death in individuals older than 65 years of age [6, 7]. According to the National Vital Statistics Report of the Centers for Disease Control, pneumonia and influenza were listed as the eighth leading causes of death in the United States in 2011 [8]. As a result, the economic burden of CAP remains significantly high, at more than $17 billion dollars annually in the United States [9].
Several risk factors have been associated with CAP, including age and comorbid diseases [10]. Furthermore, exposure to air pollution and circulating levels of sex hormones also seem to play an important role in the predisposition of some respiratory infections [11, 12]. Although some studies in animals have shown that females are more resistant than males to some bacterial infections [13, 14], others have shown that these patterns are reversed if animals are pre-exposed to environmental pollutants, such as ozone [15–20]. Incidentally, some clinical studies have reported that men are more susceptible to developing CAP and receive more intensive care than women, and show increased risk to die from pneumonia [21]. Moreover, exposure to air pollution has been associated with an increased risk for respiratory disorders due to its negative effects on lung function and immunity [22]. In this regard, long-term exposures to air pollutants, such as ozone, nitric oxide, and particulate matter in older adults have been linked with increased hospitalization rates for CAP [11, 21, 23, 24]. In addition, exposure to diverse environmental agents has been linked to negative lung health outcomes in children and adults (Table 1). The mechanisms associated with these clinical outcomes will be discussed in the following sections.
Children | Adults | ||||
---|---|---|---|---|---|
Environmental exposure | Health outcome | Sex differences | Environmental exposure | Health outcome | Sex differences |
Secondhand smoke | Pneumonia (incidence and severity) | N/A | Particulate matter (PM10) | Chronic laryngitis | Higher in males |
Air pollution | Pneumonia, Bronchitis | N/A | House biomass fuel use | Various communicable respiratory disease | Higher in women |
Household air quality | Pneumonia | Higher in males | Secondhand smoke | Community-acquired pneumonia (elderly) | N/A |
Air pollution | Outpatient visits for respiratory disease | Higher in females | Air pollution | Outpatient visits for respiratory disease | Higher in males |
Solid fuel | Pneummonia, Mortality | Higher in females | Air pollution (PM2.5, SO2, NO2) | Pneumonia | Higher in males (smokers) Higher in females (never smokers) |
Environmental tobacco smoking | Pneumonia Chronic bronchitis | N/A | UV radiation, sulfur oxides | Invasive pneumococcal disease | N/A |
Indoor air pollution (solid fuel cooking, keeping large animals) | Severe pneumonia | N/A | Tobacco smoke | Sinusitis, middle ear infections | Flight attendants |
SO2, total suspended particles | Pneumonia | N/A |
2.3. Pathogenesis of pneumonia
Pneumonia is characterized by a severe inflammation of the peripheral alveolar compartment and abnormal filling with fluid consolidation and exudation caused by infection with viruses, bacteria, and/or pathogen-related molecules. The most common cause of CAP is bacterial infection, but the disease can also be triggered by viral agents (Table 2) [6, 25, 26]. Pneumonia-causing microorganisms are classified as typical, atypical (zoonotic and non-zoonotic), Gram-negative, and viruses.
Community-acquired pneumonia can also be caused by a variety of viral infections. The most frequent viruses associated with CAP are influenza A and B, and parainfluenza. Less frequently, respiratory syncytial virus (RSV), severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus, are also responsible for CAP. Furthermore, most of these viral infections present in combination with multiple bacterial pathogens including
The main mechanism of infection in CAP is micro-aspiration from a previously colonized oropharynx, but inhalation of suspended aerosolized microorganism is the route of infection for viruses and bacterial agents, such as
CAP pathogens | Environmental associations/comorbidities |
---|---|
Nursing home resident | |
Alcoholism | |
HIV infection | |
Chronic obstructive lung disease | |
Aspiration, enteric chemical pneumonitis | |
Poor dental hygiene | |
Structural disease of the lung: (bronchiectasis, cystic fibrosis) | |
Recent influenza infection | |
Drug-resistant | Recent antibiotic therapy |
Exposure to birds | |
Contact with farm animals or parturient cats Exposure to rabbits | |
Travel to southwest USA | |
Exposure to bats | |
Congestive heart failure, mixed infections |
2.4. Gender differences in community-acquired pneumonia
Increasing evidence suggests that sex hormones play a role in the expression of genes involved in the regulation of the immune system, which in turn can impact the individual susceptibility to infectious agents, and incidence of autoimmune diseases [13, 14]. In this regard, patients suffering from systemic autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren’s syndrome, and others) are at increased risk of developing pulmonary infection, aspiration pneumonia, and bronchiolitis obliterans organizing pneumonia [40]. Furthermore, studies have shown that androgens in males can affect the immune system leading to an increased susceptibility to infection and disease caused by parasites, fungi, bacteria, and viruses. On the contrary, estrogen leads to an increase of cell-mediated and humoral immune responses in females, making them more resistant to some infectious diseases [41]. However, the role of estrogen in modulating the immune response remains controversial [42, 43].
Remarkably, physiological changes in male and female sex hormone levels (estradiol, testosterone) play important roles in human lung development, and differences in susceptibility to pulmonary infection are also present at an early age [44–47]. Gender disparities are also displayed in expression of surfactant production that appears earlier in female than male during lung development, and in the incidence of neonatal conditions of prematurity, such as respiratory distress syndrome and bronchopulmonary dysplasia [48, 49]. The earlier presence of surfactant in female neonatal lungs helps open the small airways and may contribute to their higher airflow rate observed [50]. Evidence from human studies suggests that male infants are more susceptible to lung infection, with greater associated morbidity and mortality than female infants, but the reverse is applied in children and adolescents [47, 51, 52]. Regarding respiratory tract infections (RTIs), women are more commonly affected by upper RTIs, such as sinusitis, tonsillitis, and otitis externa. On the other hand, men are at higher risk of developing otitis media, croup, and lower RTIs, including CAP [11]. Furthermore, these infections are more severe and show poorer outcomes and more complications in male than female individuals, leading to increased mortality, especially in CAP [21]. To date, the specific contributions of sex hormones or other factors, such as exposure to air pollution, socioeconomic, racial, and/or behavioral factors, obesity, and other comorbidities have only been explored in small studies [24, 53–56]. Several other factors including anatomic differences of the respiratory tract, behavioral, socioeconomic, and lifestyle factors have also been related with differences in incidence and severity of respiratory infections between genders [11, 41]. Table 1 summarizes epidemiological data on associations of sex and environmental exposures on various lung health outcomes including pneumonia in children and adults [10, 27, 57–72].
3. Pneumonia in the laboratory: animal models and mechanisms of infection
3.1. Animal models of pneumonia
Wide-ranging research is required to understand the mechanisms underlying pulmonary diseases, such as pneumonia. Studies of human populations,
A variety of species have been used as animal models of pneumonia. Even though some species, such as
Larger mammalian species, such as rabbits, piglets, and primates are ideal for specialized experiments when physiological monitoring and therapies are evaluated [82]. Currently, primates are the only species able to assess primate-specific infectious agents, but due to ethical concerns, piglets are the most frequently used model to study ventilator-associated pneumonia (VAP). Even though large mammalian animals are phylogenetically close to the human species, the disadvantages associated with their use as models is that they are only useful for a limited number of studies, and they are expensive to house and feed, slow to breed, and genetically diverse. For this reason, infections in the lung have primarily been studied in small mammalian species, predominantly rodents. Rodents are small, inexpensive, and highly reproductive. Inbred strains are preferred to investigate genetically identical groups by facilitating the use of molecular approaches to understand the mechanisms of diseases. Since studies in mice have become popular in scientific research, the creation of new studies benefit from the extensive literature available regarding genetic engineering, immunological responses to pathogens and host defenses.
3.2. Strain differences and associated mechanisms
Knowledge of differences among strains of animals in disease models can provide ideal tools for the discovery of mechanisms of disease development [83]. A strain is defined as a group of genetically identical animals. Laboratory mice are often very diverse in behavior and physiology due to a large variety of inbred, outbred, and transgenic strains produced. In laboratory mice, this is developed through inbreeding. Different mouse strains show different responses to lung infection and environmental exposures, and these can also be affected by sex and age [84]. The most common mice strains used for the study of human pneumonia are BALB/c, C57BL/6, DBA/2, 129/Sy, CBA/Ca, C3H, SJL, and A/J. In addition, a recently developed strain, collaborative cross (CC) is derived from an eight-way cross using several founder strains [85].
A study comparing susceptibility to lung infection in mice reported that, after inducing pneumococcus infection in the respiratory track of various strains, BALB/c mice, which have the ability to produce monoclonal antibodies, show no bacteremia and no lethality. Contrarily, C57BL/6 and DBA/2 mice, which are widely used inbred strains with opposite genetic susceptibility, showed 50% lethality and an intermediate response to bacteremia. Moreover, strains, such as CBA/Ca, C3H, and SJL which are highly susceptible to infection, developed acute bacteremia with 100% lethality [86]. In a similar experiment, following pulmonary
In all these species, innate immune mechanisms defend the airways from a wide array of infections that enter the lungs and cause pneumonia. Inbred laboratory mouse strains highly differ in their immune response patterns as a result of mutations and polymorphisms. As an overall rule, toll-like receptor 4 (TLR4) mutant mice, such as C3H/HeJ are more susceptible to Gram-negative infections (e.g.
Following infection, both human and mouse lungs produce immune mediators, such as cytokines, chemokines, and other components of the immune system. A regulator of IL-1β that is also highly expressed in mouse and human lungs after infection is prostaglandin E (PGE2), and its precursor enzyme cyclooxygenase-2 (COX2) [52]. Studies using depletion of alveolar macrophages have demonstrated that these contribute largely to the stimulation of pro-inflammatory cytokines, such as IL-6 and TNFα [48]. Moreover, interleukin-1β (IL-1β) is induced only by strains containing the cholesterol-dependent cytolysin, pneumolysin (PLY), a major virulence factor of pneumococci infection [51]. In addition, the levels of toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) increase after
Viruses can also lead to pneumonia. Influenza A and B viruses are the most common causes of pneumonia in adults, but other viruses can contribute to the disease development. The susceptibility of mice models to influenza viruses depends on the strain of virus used. The most commonly used strains in research are A/Puerto Rico/8/1934 (H1N1, PR8) or A/WSN/1933 (H1N1, HSN). Researchers also use several pandemic viruses, such as the 1918 H1N1 pandemic strain, highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype, certain H7 subtype viruses, a subset of low pathogenic avian influenza viruses, and the 2009 H1N1 pandemic strains. After viral infection in mice, several immunomodulatory mediators are released including IL-1β, IL-6, IL-8, MCP-1, MIP-1α/β, interferon-gamma inducible protein (IP-10) and interferon-beta (IFN-β) in a somewhat strain-specific manner [98–100].
Animal research in viral pneumonia employs either BALB/c or C57BL/6 mice [68]. The majority of laboratory mice are vulnerable to disease and death after infection, whereas, wild mice are resistant to exposure. This is due to the lack of the antiviral factor Mx1 protein in inbred strains [72]. On the other hand, it is possible for researchers to adapt strains to mouse models. DBA/2J and A/J mice are more susceptible to diseases, even with viral isolates that were not adapted to mice, than the more frequently used BALB/C and C57BL/6 strains. Even though mouse-adapted strains are important to model seasonal H1N1 and H3N2 virus infections, certain influenza viruses cause disease in mice without prior adaptation [101]. Therefore, the interpretation of research outcomes in a particular strain may not be applicable in other strains and molecular pathways in pneumonic mouse lungs may differ.
Typically, Th1 cells are important in the clearance of intracellular pathogens, whereas Th2 cells are associated with responses to parasites. C57BL/6 mice display a typical Th1-type bias to pathogens, whereas other strains, such as BALB/c, A/J, and DBA/2 mice, tend toward a Th2 response [102]. These variations may also be reflected in the M1 and M2 macrophage responses to antigen stimulation. In addition, the region
Currently, researchers are taking advantage of the phenotypic and genetic variations available in CC mice. The CC combines the genomes of eight genetically diverse founder strains, such as A/J, C57BL/6 J, 129S1/SvImJ, NOD/LtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ [85]. This genetic combination is a significant element for the study on human-host susceptibility to major diseases, including infections, such as pneumonia [105]. In a recent study, scientists used the CC mouse model to determine whether the host genetic background could impact the risk of morbidity and mortality to pneumonia caused by infection with
3.3. Sex differences in pneumonia models
It has been known for several years that sex is a contributing factor in the prevalence and development of a number of pulmonary diseases, such as pneumonia [11, 108]. Animal studies also suggest that there is a sexual dimorphism after puberty in innate and adaptive immune response genes in C57BL/6 mice, with innate immune response genes being highly upregulated in postpubertal male mice but not in female mice. In contrast, postpubertal female mice express high levels of adaptive immune response genes, and expression of these genes occurs at lower levels in postpubertal male mice [60].
Several studies in animals have reported that increase in circulating levels of estrogens may lead to reduced innate immunity, as measured by natural killer cell and macrophage activity, and a decrease of cytokine release [109–111]. Animal models of infection are the simplest tool available to study sex differences due to high availability of castrated animals and hormonal replacement therapies. Multiple studies have demonstrated that susceptibility to invasive viral, bacterial, fungal, and parasitic diseases is higher in males than in females in all age groups [57, 61, 112, 113]. The concept that males are more susceptible to lung infection is further sustained by data from mouse models of bacterial infection, such as
3.4. Sex-specific mechanisms of infection and immunity
Currently, there is limited understanding of the molecular processes that lead to either immune-suppression or stimulation during pneumonia pathogenesis in males and females. In general, females display strong humoral immune responses after infection or vaccination when compared to males [114]. This is partially due to high levels of CD4+ T cells and variations in regulatory T cells (Treg) that regulate immune responses during the menstrual cycle in women [117]. It is known that estrogen influences transcription of specific genes that alter host immunity and promotes the proliferation of Treg during the follicular phase of the ovarian cycle [89, 118]. Because estrogen regulates CD4+ T cell subsets, there is a direct effect on Th1/Th2 equilibrium known to be crucial against bacterial and viral infections. On the other hand, studies indicate that negative outcomes from infectious pulmonary diseases in males is associated with testosterone-induced immunosuppression causing a decrease in T and B cell proliferation, and immunoglobulin and cytokine production after puberty [14]. These alterations in the adaptive immune system could help explain why men are more susceptible than women to some pulmonary diseases caused by infectious agents. However, treatments for pneumonia are standardized for both men and women indicating a general lack of understanding of sex-based differences.
4. Sex hormones and lung immunity
4.1. Sex hormones and mechanisms of action
Sex and gender differences in clinical disorders are mostly driven by genetics and sex hormones. In order to understand hormonal effects not only in lung diseases, but also in other health conditions, it is essential to recognize their mechanisms of action, signaling pathways, and active metabolites. The major sex steroid hormones, such as estrogen, progesterone, and testosterone are derived from a common lipid precursor, cholesterol, by a complex series of reactions catalyzed by multiple enzymes [119]. In brief, cholesterol is converted to pregnenolone by the cytochrome P450 enzyme. Pregnenolone, which is a precursor and metabolic intermediate in the biosynthesis of the steroid hormones, can be transformed either to progesterone by the action of 3β-hydroxysteroid dehydrogenase (3β-HSD), or alternatively be converted to dehydroepiandrosterone (DHEA) via cytochrome P450c17 action. DHEA can turn into androstenedione via 3β-HSD and consequently testosterone or estrone via 17β-HSD and aromatase, respectively. Estrone may be further converted to estradiol via 17β-HSD. Testosterone can be also transformed into estradiol via aromatase.
Sex steroids are primarily produced by the gonads (ovaries and testes). Significant evidence suggest that production of sex steroids is also found in peripheral tissues of non-reproductive organs, such as the adrenal gland, heart, breast, and lung implying a dependency on the enzymes present in the organs [120, 121]. It is thought that the source of hormone production can affect the metabolism, circulation, regulation, and concentration of local steroid versus that of circulation, which can play a role in the paradoxical effects observed for some sex hormones [43, 122, 123]. One example is the “estrogen paradox”, observed in women with pulmonary hypertension. A large number of animal studies have found estrogen to be protective in the coronary circulation with better outcomes in female mice, and exasperation after ovariectomy. Contrarily, there is a higher prevalence of pulmonary hypertension in women. While some studies in humans have suggested that estrogen may increase the risk of portopulmonary hypertension, others have shown that estrogen enhances pulmonary vascular remodeling [124].
Circulating levels of testosterone range from 2 to 15 ng/ml or 6 to 50 nM in males, and less than 1.5 ng/ml or 5 nM in females throughout life. Even though men produce both estrogen and progesterone, the levels of these hormones are significantly higher in women, fluctuating from 20 pg/ml estrogen and 0.3 ng/ml progesterone in the follicular phase in non-pregnant and postmenopausal women, to 40 ng/ml estradiol and 300 ng/ml progesterone in pregnant women [43]. The significance of the oscillations of hormonal levels consists in their contribution to the local level of any sex steroids. For example, the estrogen produced in tissues may become more prominent in postmenopausal women, while the effect of progesterone may decline. At present, there is not much information available on this issue relevant to the lung.
4.2. Effect of sex hormones in immune responses and lung development
Currently, there is an increasing evidence for sex differences in incidence, morbidity, and mortality of lung diseases. Whether sex steroids play a role in modulating these differences is currently under investigation.
Estradiol levels in the fetus emerge in week 20 during the canalicular phase of lung development, and rise throughout birth [125]. Differences in estrogen levels have been observed in lung maturation, preservation, and regeneration, alveoli development and surfactant synthesis suggesting an active role of estrogen in sexual dimorphism [126–131]. Moreover, it is known that estrogen plays a complicated immunomodulatory role in humans and in animal models, suppressing inflammation in some states while enhancing it in others [116]. In animal models, estrogen blocks both B and T cell development, increases thymic atrophy, and decreases all developing T cell populations, while it enhances B cell survival in response to antigen [132–134]. In humans, hormone replacement therapy reduced the amount of T cells, while B cells were unaltered or upregulated in postmenopausal women, increasing the risk of developing B cell-dependent autoimmune diseases [123, 135]. Other studies propose that estrogen enriches the accumulation of Th1 CD4+ T cells in response to antigen in female mice [136]. It was also stated that estrogen inhibits the induction of Th1 pro-inflammatory cytokines (IL-12, IFNγ, and TNFα), while it enhances Th2 anti-inflammatory cytokines (IL-4, IL-10, and TGFβ) in female mice [137]. However, little is known about how puberty affects lung diseases later in life and how the changes in estrogen levels contribute to the pathophysiology of pulmonary diseases. This is important because estrogen can cause effects on the immune system by binding to estrogen receptors (ER) expressed by immune cells, such as B cells, T cells, and macrophages [138]. Variations in the expression of ER in the bronchial and alveolar epithelium suggest a role in estrogen signaling, which can contribute to the gender dimorphism seen in males and females [130, 131, 139, 140]. In addition, estrogen has the ability to indirectly stimulate airway and parenchymal responses by acting on airway and alveolar epithelial cells, which are structural cells [141]. In the case of infection with
5. Pneumonia and air pollution: epidemiological and experimental data
5.1. Outdoor air pollution and lung health
In the last several decades, an accumulative body of epidemiological, toxicological, and experimental evidence, including various exposure agents, times, doses, and combinations of pollutants, have linked exposure of air pollution to negative cardiovascular and pulmonary health effects [146], and infection rates (Table 1). These include increased inflammation, exacerbation of pre-existing inflammatory lung disease (e.g. asthma, wheezing, and COPD) and allergies, altered lung function and immunity, and increased susceptibility to infection and pneumonia. Extensive epidemiological evidence demonstrated inter-individual differences in the susceptibility to environmental exposures, with age, gender, and genetic polymorphisms significantly contributing to its negative health effects [12]. A summary of the most frequently found pollutants and their health effects is summarized in Table 4.
Pollutant | Health effects |
---|---|
Ozone | Decreased lung function Increased airway reactivity Increased lung inflammation Increased hospital visits for lung disease Increased mortality |
Particulate matter | Decreased lung function Increased respiratory symptoms Increased mortality |
Nitrogen dioxide | Increased airway reactivity Reduced lung function Bronchitis (children) |
Carbon monoxide | |
Sulfur dioxide | Increased respiratory mortality Increased hospital visits for lung disease Aggravation of lung disease Increased lung inflammation |
Air pollutants are generally present in the environment as a mixture of several gases and particles that are products of combustion of fossil fuels, diesel traffic, wood smoke, and other industrial processes. Some sources of domestic energy used around the world, especially in developing countries, are the result of combustion of fuels, such as wood, dung, and charcoal but also result in the generation of large amounts of indoor pollutants including small particulates (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and various hydrocarbons [147]. In this context, individuals who spent time at home, such as mothers and their children are at higher risk of developing respiratory infections [148–150]. In addition, particulate air pollution released by burning plantations has also been associated with pneumonia. For example, in Brazil (one of the main sugar cane producers), the incidence of pneumonia-related emergency department visits has found significant increase during sugar cane burning periods [151]. Air pollution in countries with high industry factory activity, such as Taiwan has also been associated with respiratory diseases, with some differences in age and gender of the patients affected. In these studies, NO and NO2 were two of the main air pollutants related to respiratory diseases, followed by PM10, PM2.5, O3, CO, and SO2. Young patients (0–15 years of age) were the most affected by air pollution and meteorology factors, followed by elder patients (age ≥66 years), and aged 16–65. A closer look at gender differences revealed that women were more affected than men in the young age group and in the eldest group, but men were more sensitive between ages 16 and 65 groups [152–155]. Other studies have also reported both women and elderly people to be more susceptible to die from air pollution than other population groups [153, 156, 157].
One of the reasons that could explain the increased mortality in women is their high vulnerability to autoimmune disorders, some of which are associated with air pollution [158]. Moreover, anatomic and physiologic differences between men and women also seem to play a role in this disparity. In general, men have higher lean body mass and water content than women, which results in an increased distribution volume of soluble substances. On the contrary, women have more relative fat mass than men, which gives them a larger distribution volume for fat-soluble substances, and most of the chemical particles in the environment are highly lipophilic. Furthermore, important sex differences in the metabolism of such substances also exist. For example, most of the CYP enzymes are regulated by sex steroids. As a result, some substances are metabolized faster in women liver cells than men, and sometimes the end products are more toxic than the original substance, causing a higher toxicity for women due to increased internal exposure [158].
Accumulating epidemiological, clinical, and experimental evidence suggests that exposure to air pollutants can have serious effects in metabolic and endocrine function, particularly in glucose metabolism [159, 160]. Air pollution, especially traffic-related exposures, NO2, tobacco smoke, and particulate matter, have been associated with obesity, type 2 diabetes, and metabolic syndrome with women showing higher susceptibility than men, and children being especially susceptible [161–164]. Studies conducted in several countries, such as Europe, America, and Asia reported strong associations among exposure to air pollutants, insulin resistance, obesity, and diabetes with women overrepresented in the affected groups [165–170]. These findings have also been recapitulated in animal models, where exposure to particulate matter resulted in increased insulin resistance followed by a high-fat diet [171–173], and these effects were associated with inflammation triggered by mechanisms involving pulmonary oxidative stress [174].
5.2. Metabolic effects of air pollution and their relationship with pneumonia
The relationship between diabetes, obesity, and susceptibility to lung infection and pneumonia has also been evaluated in several studies [175]. In these, an increased incidence and mortality from pneumococcal pneumonia, influenza, and tuberculosis was strongly associated with diabetes and obesity [176]. In this context, it is important to mention that obesity affects more women than men globally, and that a high body mass index has been directly associated with CAP risk in women [177, 178]. Animal models of bacterial infection using the leptin-deficient obese mouse have also shown higher susceptibility to pneumonia [179, 180]. Finally, an “obesity paradox” in CAP has also been reported extensively, in which obesity is associated with a higher incidence of bacterial pneumonia, but increased body mass index was associated with increased survival in patients hospitalized with CAP [181].
5.3. Genetic contributions to pneumonia risk and severity
We mentioned earlier studies reporting gender, racial, and population variability in both pneumonia incidence and outcome. Therefore, it is highly likely that these differences are the result of a complex interplay between both host and pathogen genetic backgrounds together with nongenetic factors, such as those discussed above [182]. With the recent development of fast and affordable high-throughput sequencing techniques, more studies have begun to explore the contributions of host genetics in the context of pneumonia [183–186]. The majority of these have focused on innate immune molecules, such as toll-like receptors and pro-inflammatory cytokines. Several associations of pneumonia susceptibility and severity with single nucleotide polymorphisms in the interleukin-6, interleukin-10, toll-like receptors TLR2, TLR4, and TLR9, C-reactive protein (CRP), and nitric oxide synthase 3 (NOS3) genes were reported [187–191]. We have summarized these in Table 5. Interestingly, most polymorphisms found in the cytokine genes are located in regulatory and promoter regions, where they may be affecting binding of transcription factors, such as GATA1-3, SOX, and heat shock proteins [183].
Gene | SNPs |
---|---|
C-reactive protein | rs1205 |
Interleukin-1 beta | rs16944 |
Interleukin-6 | rs1800797, rs1800795 |
Interleukin-8 | rs4073 |
Interleukin-10 | rs1800896, rs1800871, rs1800872, rs5743629 |
Nitric oxide synthase 3 | rs1799983 |
Toll-like receptor 2 | rs5743708 |
Toll-like receptor 4 | rs4986790, rs4986791 |
Toll-like receptor 9 | rs5743836 |
5.4. Pollution models of infection and pneumonia
Air pollution has been shown to exacerbate respiratory diseases, such as pneumonia. Air pollutants that reach the respiratory tract are currently responsible for its genesis, especially particulate matter having an aerodynamic diameter equal to or less than 10 μm, sulfur dioxide (SO2), ground level ozone (O3), nitrogen dioxide (NO2), and carbon monoxide (CO) [192, 193]. However, these pollutants may also increase the risk for pneumonia by altering the function of alveolar macrophages, epithelial cells, mucociliary clearance mechanisms, particle transport, and local immunity in the lungs [194]. Because of methodological difficulties and ethical issues, there are a limited number of studies on the effects of controlled pollutant exposure and infection in humans. It has now been almost 50 years since the “infectivity model” has been created. This model is based on the study of the effects of pollutants on pulmonary activity after pollutant exposure with disease and mortality as end-points in animals, particularly rodents [147].
The infectivity model is used by researchers to determine the amount and concentration of pollutants at which the immune system is compromised and disease is developed. This is accomplished by challenging animals with virulent agents either before or after exposure to different concentrations of the pollutant. Exposure to NO2 before and after infectious challenge in mice show significantly higher death rates [195]. Moreover, mice infected with
There are several pollution models of pneumonia infection combined with particulate matter [199], SO2 [200], CO [201], and other common air pollutants. These models generally involve a higher concentration of pollutants than would be normally found in the atmosphere. This is often necessary because a higher dose of most pollutants is required for rodents versus humans to reach comparable concentrations in the distal lung and generating comparable effects on lung function and immunity.
Ozone exposure can impair breathing, induce coughing, reduce lung function, and trigger lung diseases, such as pneumonia. The effect of ozone exposure has been associated with damage of the entire respiratory epithelia and lung immunity [202]. A study showed that mice infected with
6. Conclusion
Regulation of the lung inflammatory response is critical to the successful outcome of pneumonia. Exposure to air pollutants has been linked to negative lung health outcomes, and sex hormones have been shown to mediate the lung immune response, especially during lung infection. The negative impact of air pollution on lung health, both in the short and long term, is now well accepted, and air quality indexes or scales are available to alert individuals when the air quality is at harmful levels. In this chapter, we have discussed experimental and epidemiological evidence on pneumonia infection incidence in different populations, influences of air pollution and environmental exposures, and sex-specific mechanisms involving male and female hormones in the context of lung immunity. This information could help researchers better explain the differences observed in pneumonia susceptibility and lung health outcomes in men versus women. Understanding the biological basis of these differences is critical for the development of more effective prevention and management strategies for pneumonia in men and women, and could help in the development of better treatment options for these patients.
References
- 1.
Card JW, Zeldin DC. Hormonal influences on lung function and response to environmental agents: Lessons from animal models of respiratory disease. Proceedings of the American Thoracic Society. 2009; 6 (7):588-595 - 2.
Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC. The impact of sex and sex hormones on lung physiology and disease: Lessons from animal studies. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2007; 293 (2):L272-L278 - 3.
Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Seminars in Respiratory and Critical Care Medicine. 2009; 30 (1):3-9 - 4.
Chalmers JD. The modern diagnostic approach to community-acquired pneumonia in adults. Seminars in Respiratory and Critical Care Medicine. 2016; 37 (6):876-885 - 5.
Brar NK, Niederman MS. Management of community-acquired pneumonia: A review and update. Therapeutic Advances in Respiratory Disease. 2011; 5 (1):61-78 - 6.
Nair GB, Niederman MS. Community-acquired pneumonia: An unfinished battle. The Medical Clinics of North America. 2011; 95 (6):1143-1161 - 7.
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases. 2007; 44 (Suppl 2):S27-S72 - 8.
Kochanek KD, Murphy SL, Xu J. Deaths: Final data for 2011. National Vital Statistics Reports. 2015; 63 (3):1-120 - 9.
File TM, Jr., Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgraduate Medicine. 2010; 122 (2):130-141 - 10.
Almirall J, Bolibar I, Serra-Prat M, Roig J, Hospital I, Carandell E, et al. New evidence of risk factors for community-acquired pneumonia: A population-based study. European Respiratory Journal. 2008; 31 (6):1274-1284 - 11.
Falagas ME, Mourtzoukou EG, Vardakas KZ. Sex differences in the incidence and severity of respiratory tract infections. Respiratory Medicine. 2007; 101 (9):1845-1863 - 12.
Silveyra P, Floros J. Air pollution and epigenetics: Effects on SP-A and innate host defence in the lung. Swiss Medical Weekly. 2012; 142 :w13579 - 13.
Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. The Lancet Infectious Diseases. 2010; 10 (5):338-349 - 14.
Fish EN. The X-files in immunity: Sex-based differences predispose immune responses. Nature Reviews Immunology. 2008; 8 (9):737-744 - 15.
Durrani F, Phelps DS, Weisz J, Silveyra P, Hu S, Mikerov AN, et al. Gonadal hormones and oxidative stress interaction differentially affects survival of male and female mice after lung Klebsiella pneumoniae infection. Experimental Lung Research. 2012;38 (4):165-172 - 16.
Mikerov AN, Hu S, Durrani F, Gan X, Wang G, Umstead TM, et al. Impact of sex and ozone exposure on the course of pneumonia in wild type and SP-A (−/−) mice. Microbial Pathogenesis. 2012; 52 (4):239-249 - 17.
Mikerov AN, Cooper TK, Wang G, Hu S, Umstead TM, Phelps DS, et al. Histopathologic evaluation of lung and extrapulmonary tissues show sex differences in Klebsiella pneumoniae -infected mice under different exposure conditions. International Journal of Physiology, Pathophysiology and Pharmacology. 2011;3 (3):176-190 - 18.
Mikerov AN, Gan X, Umstead TM, Miller L, Chinchilli VM, Phelps DS, et al. Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection. Respiratory Research. 2008;9 :24 - 19.
Mikerov AN, Haque R, Gan X, Guo X, Phelps DS, Floros J. Ablation of SP-A has a negative impact on the susceptibility of mice to Klebsiella pneumoniae infection after ozone exposure: Sex differences. Respiratory Research. 2008;9 :77 - 20.
Mikerov AN, Umstead TM, Gan X, Huang W, Guo X, Wang G, et al. Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2008; 294 (1):L121-L130 - 21.
Kaplan V, Angus DC, Griffin MF, Clermont G, Scott Watson R, Linde-Zwirble WT. Hospitalized community-acquired pneumonia in the elderly: Age- and sex-related patterns of care and outcome in the United States. American Journal of Respiratory and Critical Care Medicine. 2002; 165 (6):766-772 - 22.
Pope CA. Particulate air pollution and lung function. American Journal of Respiratory and Critical Care Medicine. 2014; 190 (5):485-486 - 23.
Zanobetti A, Woodhead M. Air pollution and pneumonia: The “old man”; has a new “friend”. American Journal of Respiratory and Critical Care Medicine. 2010; 181 :5-6; United States - 24.
Neupane B, Jerrett M, Burnett RT, Marrie T, Arain A, Loeb M. Long-term exposure to ambient air pollution and risk of hospitalization with community-acquired pneumonia in older adults. American Journal of Respiratory and Critical Care Medicine. 2010; 181 (1):47-53 - 25.
de Roux A, Marcos MA, Garcia E, Mensa J, Ewig S, Lode H, et al. Viral community-acquired pneumonia in nonimmunocompromised adults. Chest. 2004; 125 (4):1343-1351 - 26.
Cunha BA. The atypical pneumonias: clinical diagnosis and importance. Clinical Microbiology and Infection. 2006; 12 (Suppl 3):12-24 - 27.
Bassani DG, Jha P, Dhingra N, Kumar R. Child mortality from solid-fuel use in India: A nationally-representative case-control study. BMC Public Health. 2010; 10 :491 - 28.
Arancibia F, Bauer TT, Ewig S, Mensa J, Gonzalez J, Niederman MS, et al. Community-acquired pneumonia due to gram-negative bacteria and Pseudomonas aeruginosa : Incidence, risk, and prognosis. Archives of Internal Medicine. 2002;162 (16):1849-1858 - 29.
Wunderink RG, Waterer GW. Community-acquired pneumonia: Pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infectious Disease Clinics of North America. 2004; 18 (4):743-759, vii - 30.
Torres A, Peetermans WE, Viegi G, Blasi F. Risk factors for community-acquired pneumonia in adults in Europe: A literature review. Thorax. 2013; 68 (11):1057-1065 - 31.
Shea KM, Edelsberg J, Weycker D, Farkouh RA, Strutton DR, Pelton SI. Rates of pneumococcal disease in adults with chronic medical conditions. Open Forum Infectious Diseases. 2014; 1 (1):ofu024 - 32.
Pelton SI, Shea KM, Weycker D, Farkouh RA, Strutton DR, Edelsberg J. Rethinking risk for pneumococcal disease in adults: The role of risk stacking. Open Forum Infectious Diseases. 2015; 2 (1):ofv020 - 33.
Dye JA, Adler KB. Effects of cigarette smoke on epithelial cells of the respiratory tract. Thorax. 1994; 49 (8):825-834 - 34.
Almirall J, Blanquer J, Bello S. Community-acquired pneumonia among smokers. Archivos de Bronconeumología. 2014; 50 (6):250-254 - 35.
Almirall J, Serra-Prat M, Bolíbar I, Palomera E, Roig J, Hospital I, et al. Passive smoking at home is a risk factor for community-acquired pneumonia in older adults: A population-based case–control study. BMJ Open. 2014; 4 (6):e005133 - 36.
Nelson S, Kolls JK. Alcohol, host defence and society. Nature Reviews Immunology. 2002; 2 (3):205-209 - 37.
Rodriguez-Pecci MS, Carlson D, Montero-Tinnirello J, Parodi RL, Montero A, Greca AA. Nutritional status and mortality in community acquired pneumonia. Medicina (B Aires). 2010; 70 (2):120-126 - 38.
Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia. Respirology. 2011; 16 (4):611-616 - 39.
Orlov AM, Bakulin IG, Mazo VK. Deficiency of selenium in pneumonia: An accident or regularity? Problem of Nutriciology and Gastroenterology. Eksp Klin Gastroenterol. 2013;(2):20-27 - 40.
Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD. Pulmonary manifestations of systemic autoimmune diseases. Maedica (Buchar). 2011; 6 (3):224-229 - 41.
Klein SL. The effects of hormones on sex differences in infection: From genes to behavior. Neuroscience & Biobehavioral Reviews. 2000; 24 (6):627-638 - 42.
Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocrine Reviews. 2012; 33 (1):1-47 - 43.
Sathish V, Martin YN, Prakash YS. Sex steroid signaling: Implications for lung diseases. Pharmacology and Therapeutics. 2015; 150 :94-108 - 44.
Pasqualini JR. Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments. Journal of Steroid Biochemistry and Molecular Biology. 2005; 97 (5):401-415 - 45.
Milewich L, Kaimal V, Shaw CB, Johnson AR. Androstenedione metabolism in human lung fibroblasts. Journal of Steroid Biochemistry. 1986; 24 (4):893-897 - 46.
Silveyra P. Chapter 9: Developmental lung disease. In: Hemnes AR, editor. Gender, Sex Hormones and Respiratory Disease A Comprehensive Guide; Springer International Publishing, Switzerland. 2016; p. 243 - 47.
Tettelin H, Nelson KE, Paulsen IT, Eisen JA, Read TD, Peterson S, et al. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae . Science. 2001;293 (5529):498-506 - 48.
Xu F, Droemann D, Rupp J, Shen H, Wu X, Goldmann T, et al. Modulation of the inflammatory response to Streptococcus pneumoniae in a model of acute lung tissue infection. American Journal of Respiratory Cell and Molecular Biology. 2008;39 (5):522-529 - 49.
May C, Patel S, Kennedy C, Pollina E, Rafferty GF, Peacock JL, et al. Prediction of bronchopulmonary dysplasia. Archives of Disease in Childhood‐Fetal and Neonatal Edition. 2011; 96 (6):F410-F416 - 50.
Rai P, Parrish M, Tay IJ, Li N, Ackerman S, He F, et al. Streptococcus pneumoniae secretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells. Proceedings of the National Academy of Sciences of the United States of America. 2015;112 (26):E3421-E3430 - 51.
Fatykhova D, Rabes A, Machnik C, Guruprasad K, Pache F, Berg J, et al. Serotype 1 and 8 pneumococci evade sensing by inflammasomes in human lung tissue. PLoS One. 2015; 10 (8):e0137108 - 52.
Szymanski KV, Toennies M, Becher A, Fatykhova D, N'Guessan PD, Gutbier B, et al. Streptococcus pneumoniae -induced regulation of cyclooxygenase-2 in human lung tissue. European Respiratory Journal. 2012;40 (6):1458-1467 - 53.
Haenle MM, Brockmann SO, Kron M, Bertling U, Mason RA, Steinbach G, et al. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health. 2006; 6 :233 - 54.
Rosenberg HM, Maurer JD, Sorlie PD, Johnson NJ, MacDorman MF, Hoyert DL, et al. Quality of death rates by race and Hispanic origin: A summary of current research, 1999. Vital and Health Statistics Series 2. 1999;(128):1-13 - 55.
Wiese AD, Grijalva CG, Zhu Y, Mitchel EF, Griffin MR. Changes in childhood pneumonia hospitalizations by race and sex associated with pneumococcal conjugate vaccines. Emerging Infectious Disease. 2016; 22 (6):1109 - 56.
Pathak EB. Mortality among black men in the USA. Journal of Racial and Ethnic Health Disparities. 2017; 4 :1-12 - 57.
Jensen-Fangel S, Mohey R, Johnsen SP, Andersen PL, Sørensen HT, Ostergaard L. Gender differences in hospitalization rates for respiratory tract infections in Danish youth. Scandinavian Journal of Infectious Diseases. 2004; 36 (1):31-36 - 58.
Fleisher B, Kulovich MV, Hallman M, Gluck L. Lung profile: Sex differences in normal pregnancy. Obstetrics & Gynecology. 1985; 66 (3):327-330 - 59.
Doershuk CF, Fisher BJ, Matthews LW. Specific airway resistance from the perinatal period into adulthood. Alterations in childhood pulmonary disease. American Review of Respiratory Diseases. 1974; 109 (4):452-457 - 60.
Lamason R, Zhao P, Rawat R, Davis A, Hall JC, Chae JJ, et al. Sexual dimorphism in immune response genes as a function of puberty. BMC Immunology. 2006; 7 :2 - 61.
Offner PJ, Moore EE, Biffl WL. Male gender is a risk factor for major infections after surgery. Archives of Surgery. 1999; 134 (9):935-938; discussion 8-40 - 62.
Marriott I, Huet-Hudson YM. Sexual dimorphism in innate immune responses to infectious organisms. Immunologic Research. 2006; 34 (3):177-192 - 63.
Katanoda K, Sobue T, Satoh H, Tajima K, Suzuki T, Nakatsuka H, et al. An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. Journal of Epidemiology. 2011; 21 (2):132-143 - 64.
White AN, Ng V, Spain CV, Johnson CC, Kinlin LM, Fisman DN. Let the sun shine in: Effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania. BMC Infectious Diseases. 2009; 9 :196 - 65.
Suzuki M, Thiem VD, Yanai H, Matsubayashi T, Yoshida LM, Tho LH, et al. Association of environmental tobacco smoking exposure with an increased risk of hospital admissions for pneumonia in children under 5 years of age in Vietnam. Thorax. 2009; 64 (6):484-489 - 66.
Ebbert JO, Croghan IT, Schroeder DR, Murawski J, Hurt RD. Association between respiratory tract diseases and secondhand smoke exposure among never smoking flight attendants: A cross-sectional survey. Environmental Health. 2007; 6 :28 - 67.
Mahalanabis D, Gupta S, Paul D, Gupta A, Lahiri M, Khaled MA. Risk factors for pneumonia in infants and young children and the role of solid fuel for cooking: A case-control study. Epidemiology and Infection. 2002; 129 (1):65-71 - 68.
Zanobetti A, Schwartz J, Gold D. Are there sensitive subgroups for the effects of airborne particles? Environmental Health Perspectives. 2000; 108 (9):841-845 - 69.
Kramer U, Behrendt H, Dolgner R, Ranft U, Ring J, Willer H, et al. Airway diseases and allergies in East and West German children during the first 5 years after reunification: Time trends and the impact of sulphur dioxide and total suspended particles. International Journal of Epidemiology. 1999; 28 (5):865-873 - 70.
Gergen PJ, Fowler JA, Maurer KR, Davis WW, Overpeck MD. The burden of environmental tobacco smoke exposure on the respiratory health of children 2 months through 5 years of age in the United States: Third National Health and Nutrition Examination Survey, 1988 to 1994. Pediatrics. 1998; 101 (2):E8 - 71.
Lopez Bravo IM, Sepulveda H, Valdes I. Acute respiratory illnesses in the first 18 months of life. Revista Panamericana de Salud Pública. 1997; 1 (1):9-17 - 72.
Staeheli P, Grob R, Meier E, Sutcliffe JG, Haller O. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Molecular and Cellular Biology. 1988; 8 (10):4518-4523 - 73.
Mizgerd JP, Skerrett SJ. Animal models of human pneumonia. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2008; 294 (3):L387-L398 - 74.
López Hernández Y, Yero D, Pinos-Rodríguez JM, Gibert I. Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens. Frontiers in Microbiology. 2015; 6 :38 - 75.
Ali S, Champagne DL, Spaink HP, Richardson MK. Zebrafish embryos and larvae: A new generation of disease models and drug screens. Birth Defects Research. Part C, Embryo Today. 2011; 93 (2):115-133 - 76.
Redd MJ, Kelly G, Dunn G, Way M, Martin P. Imaging macrophage chemotaxis in vivo: Studies of microtubule function in zebrafish wound inflammation. Cell Motility and the Cytoskeleton. 2006; 63 (7):415-422 - 77.
Meeker ND, Trede NS. Immunology and zebrafish: Spawning new models of human disease. Developmental & Comparative Immunology. 2008; 32 (7):745-757 - 78.
Meijer AH, Spaink HP. Host-pathogen interactions made transparent with the zebrafish model. Current Drug Targets. 2011; 12 (7):1000-1017 - 79.
Alper S, McElwee MK, Apfeld J, Lackford B, Freedman JH, Schwartz DA. The Caenorhabditis elegans germ line regulates distinct signaling pathways to control lifespan and innate immunity. Journal of Biological Chemistry. 2010;285 (3):1822-1828 - 80.
Lemaitre B, Hoffmann J. The host defense of Drosophila melanogaster . Annual Review of Immunology. 2007;25 :697-743 - 81.
Klein SL, Flanagan KL. Sex differences in immune responses. Nature Reviews Immunology. 2016; 16 (10):626-638 - 82.
Hraiech S, Papazian L, Rolain JM, Bregeon F. Animal models of polymicrobial pneumonia. Drug Design, Development and Therapy. 2015; 9 :3279-3292 - 83.
Davis JK, Parker RF, White H, Dziedzic D, Taylor G, Davidson MK, et al. Strain differences in susceptibility to murine respiratory mycoplasmosis in C57BL/6 and C3H/HeN mice. Infection and Immunity. 1985; 50 (3):647-654 - 84.
Vancza EM, Galdanes K, Gunnison A, Hatch G, Gordon T. Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled ozone. Toxicological Sciences. 2009; 107 (2):535-543 - 85.
Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, et al. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics. 2004; 36 (11):1133-1137 - 86.
Gingles NA, Alexander JE, Kadioglu A, Andrew PW, Kerr A, Mitchell TJ, et al. Role of genetic resistance in invasive pneumococcal infection: Identification and study of susceptibility and resistance in inbred mouse strains. Infection and Immunity. 2001; 69 (1):426-434 - 87.
Schurr JR, Young E, Byrne P, Steele C, Shellito JE, Kolls JK. Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria. Infection and Immunity. 2005; 73 (1):532-545 - 88.
Lee-Lewis H, Anderson DM. Absence of inflammation and pneumonia during infection with nonpigmented Yersinia pestis reveals a new role for the pgm locus in pathogenesis. Infection and Immunity. 2010; 78 (1):220-230 - 89.
Walzer PD, Powell RD, Yoneda K. Experimental Pneumocystis carinii pneumonia in different strains of cortisonized mice. Infection and Immunity. 1979; 24 (3):939-947 - 90.
Brieland J, Freeman P, Kunkel R, Chrisp C, Hurley M, Fantone J, et al. Replicative Legionella pneumophila lung infection in intratracheally inoculated A/J mice. A murine model of human Legionnaires' disease. American Journal of Pathology. 1994;145 (6):1537-1546 - 91.
De Vooght V, Vanoirbeek JA, Luyts K, Haenen S, Nemery B, Hoet PH. Choice of mouse strain influences the outcome in a mouse model of chemical-induced asthma. PLoS One. 2010; 5 (9):e12581 - 92.
Wieland CW, van Lieshout MH, Hoogendijk AJ, van der Poll T. Host defence during Klebsiella pneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2. European Respiratory Journal. 2011;37 (4):848-857 - 93.
Wetsel RA, Fleischer DT, Haviland DL. Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5′-exon. Journal of Biological Chemistry. 1990; 265 (5):2435-2440 - 94.
Sellers RS, Clifford CB, Treuting PM, Brayton C. Immunological variation between inbred laboratory mouse strains: Points to consider in phenotyping genetically immunomodified mice. Veterinary Pathology. 2012; 49 (1):32-43 - 95.
Makrigiannis AP, Anderson SK. The murine Ly49 family: Form and function. Archivum Immunologiae et Therapiae Experimentalis (Warsz). 2001; 49 (1):47-50 - 96.
Tokairin Y, Shibata Y, Sata M, Abe S, Takabatake N, Igarashi A, et al. Enhanced immediate inflammatory response to Streptococcus pneumoniae in the lungs of mice with pulmonary emphysema. Respirology. 2008;13 (3):324-332 - 97.
Kadioglu A, Weiser JN, Paton JC, Andrew PW. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nature Reviews Microbiology. 2008;6 (4):288-301 - 98.
Knepper J, Schierhorn KL, Becher A, Budt M, Tönnies M, Bauer TT, et al. The novel human influenza A(H7N9) virus is naturally adapted to efficient growth in human lung tissue. MBio. 2013; 4 (5):e00601-e00613 - 99.
Weinheimer VK, Becher A, Tönnies M, Holland G, Knepper J, Bauer TT, et al. Influenza A viruses target type II pneumocytes in the human lung. Journal of Infectious Diseases. 2012; 206 (11):1685-1694 - 100.
Wu W, Zhang W, Booth JL, Metcalf JP. Influenza A(H1N1)pdm09 virus suppresses RIG-I initiated innate antiviral responses in the human lung. PLoS One. 2012; 7 (11):e49856 - 101.
Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: The key to pneumococcal disease. Lancet Infectious Diseases. 2004;4 (3):144-154 - 102.
Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. Journal of Immunology. 2000; 164 (12):6166-6173 - 103.
Denny P, Hopes E, Gingles N, Broman KW, McPheat W, Morten J, et al. A major locus conferring susceptibility to infection by Streptococcus pneumoniae in mice. Mammalian Genome. 2003;14 (7):448-453 - 104.
Yamamoto Y, Okubo S, Klein TW, Onozaki K, Saito T, Friedman H. Binding of Legionella pneumophila to macrophages increases cellular cytokine mRNA. Infection and Immunity. 1994;62 (9):3947-3956 - 105.
Lorè NI, Iraqi FA, Bragonzi A. Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice. BMC Genetics. 2015;16 :106 - 106.
Vered K, Durrant C, Mott R, Iraqi FA. Susceptibility to Klebsiella pneumonaie infection in collaborative cross mice is a complex trait controlled by at least three loci acting at different time points. BMC Genomics. 2014; 15 :865 - 107.
The Collaborative Cross: A powerful systems genetics tool. 2009 [Available from: https://www.jax.org/news-and-insights/2009/april/the-collaborative-cross-a-powerful-systems-genetics-tool ] - 108.
WHO. Sex, gender and influenza. 2010 [Available from: http://apps.who.int/iris/bitstream/10665/44401/1/9789241500111_eng.pdf ] - 109.
Kita E, Takahashi S, Yasui K, Kashiba S. Effect of estrogen (17 beta-estradiol) on the susceptibility of mice to disseminated gonococcal infection. Infection and Immunity. 1985; 49 (1):238-243 - 110.
Pung OJ, Luster MI. Toxoplasma gondii : Decreased resistance to infection in mice due to estrogen. Experimental Parasitology. 1986;61 (1):48-56 - 111.
Pung OJ, Tucker AN, Vore SJ, Luster MI. Influence of estrogen on host resistance: Increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2. Infection and Immunity. 1985; 50 (1):91-96 - 112.
Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM. Male gender is associated with increased risk for postinjury pneumonia. Shock. 2004; 21 (5):410-414 - 113.
Gutiérrez F, Masiá M, Mirete C, Soldán B, Rodríguez JC, Padilla S, et al. The influence of age and gender on the population-based incidence of community-acquired pneumonia caused by different microbial pathogens. Journal of Infection. 2006; 53 (3):166-174 - 114.
Kadioglu A, Cuppone AM, Trappetti C, List T, Spreafico A, Pozzi G, et al. Sex-based differences in susceptibility to respiratory and systemic pneumococcal disease in mice. Journal of Infectious Diseases. 2011; 204 (12):1971-1979 - 115.
Guilbault C, Stotland P, Lachance C, Tam M, Keller A, Thompson-Snipes L, et al. Influence of gender and interleukin-10 deficiency on the inflammatory response during lung infection with Pseudomonas aeruginosa in mice. Immunology. 2002;107 (3):297-305 - 116.
Wang Y, Cela E, Gagnon S, Sweezey NB. Estrogen aggravates inflammation in Pseudomonas aeruginosa pneumonia in cystic fibrosis mice. Respiratory Research. 2010;11 :166 - 117.
Leone M, Textoris J, Capo C, Mege J-L. Sex Hormones and Bacterial Infections: IntechOpen. Rijeka, Croatia; 2012 - 118.
Aronica SM, Katzenellenbogen BS. Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. Molecular Endocrinology. 1993; 7 (6):743-752 - 119.
Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine Reviews. 2004; 25 (6):947-970 - 120.
Labrie F. Extragonadal synthesis of sex steroids: Intracrinology. Annales d'Endocrinologie (Paris). 2003; 64 (2):95-107 - 121.
Luu-The V, Labrie F. The intracrine sex steroid biosynthesis pathways. Progress in Brain Research. 2010; 181 :177-192 - 122.
Foderaro A, Ventetuolo CE. Pulmonary arterial hypertension and the sex hormone paradox. Current Hypertension Reports. 2016; 18 (11):84 - 123.
Straub RH. The complex role of estrogens in inflammation. Endocrine Reviews. 2007; 28 (5):521-574 - 124.
Umar S, Rabinovitch M, Eghbali M. Estrogen paradox in pulmonary hypertension: Current controversies and future perspectives. American Journal of Respiratory and Critical Care Medicine. 2012; 186 (2):125-131 - 125.
Seaborn T, Simard M, Provost PR, Piedboeuf B, Tremblay Y. Sex hormone metabolism in lung development and maturation. Trends in Endocrinology and Metabolism. 2010; 21 (12):729-738 - 126.
Massaro GD, Mortola JP, Massaro D. Sexual dimorphism in the architecture of the lung's gas-exchange region. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92 (4):1105-1107 - 127.
Massaro GD, Mortola JP, Massaro D. Estrogen modulates the dimensions of the lung's gas-exchange surface area and alveoli in female rats. American Journal of Physiology. 1996; 270 (1 Pt 1):L110-L114 - 128.
Massaro D, Massaro GD. Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2004; 287 (6):L1154-L1159 - 129.
Massaro D, Clerch LB, Massaro GD. Estrogen receptor-alpha regulates pulmonary alveolar loss and regeneration in female mice: Morphometric and gene expression studies. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007; 293 (1):L222-L228 - 130.
Patrone C, Cassel TN, Pettersson K, Piao YS, Cheng G, Ciana P, et al. Regulation of postnatal lung development and homeostasis by estrogen receptor beta. Molecular and Cellular Biology. 2003; 23 (23):8542-8552 - 131.
Liu D, Hinshelwood MM, Giguère V, Mendelson CR. Estrogen related receptor-alpha enhances surfactant protein-A gene expression in fetal lung type II cells. Endocrinology. 2006; 147 (11):5187-5195 - 132.
Lang TJ. Estrogen as an immunomodulator. Clinical Immunology. 2004; 113 (3):224-230 - 133.
Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. Journal of Clinical Investigation. 2002; 109 (12):1625-1633 - 134.
Grimaldi CM, Hicks R, Diamond B. B cell selection and susceptibility to autoimmunity. Journal of Immunology. 2005; 174 (4):1775-1781 - 135.
Gompel A, Piette JC. Systemic lupus erythematosus and hormone replacement therapy. Menopause International. 2007; 13 (2):65-70 - 136.
Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, et al. Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. European Journal of Immunology. 2003; 33 (2):512-521 - 137.
Salem ML. Estrogen, a double-edged sword: Modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Current Drug Targets. Inflammation and Allergy. 2004; 3 (1):97-104 - 138.
Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clinical Reviews in Allergy & Immunology. 2011; 40 (1):66-73 - 139.
Carvalho O, Gonçalves C. Expression of oestrogen receptors in foetal lung tissue of mice. Anatomia, Histologia, Embryologia. 2012; 41 (1):1-6 - 140.
Morani A, Warner M, Gustafsson JA. Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. Journal of Internal Medicine. 2008; 264 (2):128-142 - 141.
Draijer C, Hylkema MN, Boorsma CE, Klok PA, Robbe P, Timens W, et al. Sexual maturation protects against development of lung inflammation through estrogen. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2016; 310 (2):L166-L174 - 142.
Dammann CE, Ramadurai SM, McCants DD, Pham LD, Nielsen HC. Androgen regulation of signaling pathways in late fetal mouse lung development. Endocrinology. 2000; 141 (8):2923-2929 - 143.
Kimura Y, Suzuki T, Kaneko C, Darnel AD, Akahira J, Ebina M, et al. Expression of androgen receptor and 5alpha-reductase types 1 and 2 in early gestation fetal lung: A possible correlation with branching morphogenesis. Clinical Science (London). 2003; 105 (6):709-713 - 144.
Volpe MV, Ramadurai SM, Mujahid S, Vong T, Brandao M, Wang KT, et al. Regulatory interactions between androgens, Hoxb5, and TGF β signaling in murine lung development. BioMed Research International. 2013; 2013 :320249 - 145.
Bresson E, Seaborn T, Côté M, Cormier G, Provost PR, Piedboeuf B, et al. Gene expression profile of androgen modulated genes in the murine fetal developing lung. Reproductive Biology and Endocrinology. 2010; 8 :2 - 146.
WHO. Ambient (outdoor) air quality and health. 2016 [Available from: http://www.who.int/mediacentre/factsheets/fs313/en/ ] - 147.
Chauhan AJ, Johnston SL. Air pollution and infection in respiratory illness. British Medical Bulletin. 2003; 68 :95-112 - 148.
Collings DA, Sithole SD, Martin KS. Indoor woodsmoke pollution causing lower respiratory disease in children. Tropical Doctor. 1990; 20 (4):151-155 - 149.
Pandey MR. Domestic smoke pollution and chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax. 1984; 39 (5):337-339 - 150.
Armstrong JR, Campbell H. Indoor air pollution exposure and lower respiratory infections in young Gambian children. International Journal of Epidemiology. 1991; 20 (2):424-429 - 151.
Arbex MA, Pereira LA, Carvalho-Oliveira R, Saldiva PH, Braga AL. The effect of air pollution on pneumonia-related emergency department visits in a region of extensive sugar cane plantations: A 30-month time-series study. Journal of Epidemiology & Community Health. 2014; 68 (7):669-674 - 152.
Wang KY, Chau TT. An association between air pollution and daily outpatient visits for respiratory disease in a heavy industry area. PLoS One. 2013; 8 (10):e75220 - 153.
Makri A, Stilianakis NI. Vulnerability to air pollution health effects. International Journal of Hygiene and Environmental Health. 2008; 211 (3-4):326-336 - 154.
Ostro B, Lipsett M, Reynolds P, Goldberg D, Hertz A, Garcia C, et al. Long-term exposure to constituents of fine particulate air pollution and mortality: Results from the California Teachers Study. Environmental Health Perspectives. 2010; 118 (3):363-369 - 155.
Wen M, Gu D. Air pollution shortens life expectancy and health expectancy for older adults: The case of China. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2012; 67 (11):1219-1229 - 156.
Oiamo TH, Luginaah IN. Extricating sex and gender in air pollution research: A community-based study on cardinal symptoms of exposure. International Journal of Environmental Research and Public Health. 2013; 10 (9):3801-3817 - 157.
Westergaard N, Gehring U, Slama R, Pedersen M. Ambient air pollution and low birth weight—Are some women more vulnerable than others? Environment International. 2017 - 158.
Butter ME. Are women more vulnerable to environmental pollution? Journal of Human Ecology: Kamla-Raj. 2006; 20 :221-336 - 159.
Rajagopalan S, Brook RD. Air pollution and type 2 diabetes: Mechanistic insights. Diabetes. 2012; 61 (12):3037-3045 - 160.
Kodavanti UP. Air pollution and insulin resistance: Do all roads lead to Rome? Diabetes. 2015; 64 (3):712-714 - 161.
Rao X, Montresor-Lopez J, Puett R, Rajagopalan S, Brook RD. Ambient air pollution: An emerging risk factor for diabetes mellitus. Current Diabetes Reports. 2015; 15 (6):603 - 162.
Brook RD, Cakmak S, Turner MC, Brook JR, Crouse DL, Peters PA, et al. Long-term fine particulate matter exposure and mortality from diabetes in Canada. Diabetes Care. 2013; 36 (10):3313-3320 - 163.
Alderete TL, Habre R, Toledo-Corral CM, Berhane K, Chen Z, Lurmann FW, et al. Longitudinal associations between ambient air pollution with insulin sensitivity, β-cell function, and adiposity in Los Angeles Latino children. Diabetes. 2017. In press - 164.
Meo SA, Memon AN, Sheikh SA, Rouq FA, Usmani AM, Hassan A, et al. Effect of environmental air pollution on type 2 diabetes mellitus. European Review for Medical and Pharmacological Sciences. 2015; 19 (1):123-128 - 165.
Brook RD, Jerrett M, Brook JR, Bard RL, Finkelstein MM. The relationship between diabetes mellitus and traffic-related air pollution. Journal of Occupational and Environmental Medicine. 2008; 50 (1):32-38 - 166.
Krämer U, Herder C, Sugiri D, Strassburger K, Schikowski T, Ranft U, et al. Traffic-related air pollution and incident type 2 diabetes: Results from the SALIA cohort study. Environmental Health Perspectives. 2010; 118 (9):1273-1279 - 167.
Pearson JF, Bachireddy C, Shyamprasad S, Goldfine AB, Brownstein JS. Association between fine particulate matter and diabetes prevalence in the U.S. Diabetes Care. 2010; 33 (10):2196-2201 - 168.
Puett RC, Hart JE, Schwartz J, Hu FB, Liese AD, Laden F. Are particulate matter exposures associated with risk of type 2 diabetes? Environmental Health Perspectives. 2011; 119 (3):384-389 - 169.
Andersen ZJ, Raaschou-Nielsen O, Ketzel M, Jensen SS, Hvidberg M, Loft S, et al. Diabetes incidence and long-term exposure to air pollution: A cohort study. Diabetes Care. 2012; 35 (1):92-98 - 170.
Jerrett M, Brook R, White LF, Burnett RT, Yu J, Su J, et al. Ambient ozone and incident diabetes: A prospective analysis in a large cohort of African American women. Environment International. 2017; 102 :42-47 - 171.
Sun Q, Yue P, Deiuliis JA, Lumeng CN, Kampfrath T, Mikolaj MB, et al. Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity. Circulation. 2009; 119 (4):538-546 - 172.
Goettems-Fiorin PB, Grochanke BS, Baldissera FG, Dos Santos AB, Homem de Bittencourt PI, Ludwig MS, et al. Fine particulate matter potentiates type 2 diabetes development in high-fat diet-treated mice: Stress response and extracellular to intracellular HSP70 ratio analysis. Journal of Physiology and Biochemistry. 2016; 72 (4):643-656 - 173.
Zhong J, Allen K, Rao X, Ying Z, Braunstein Z, Kankanala SR, et al. Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. Inhalation Toxicology. 2016; 28 (9):383-392 - 174.
Haberzettl P, O'Toole TE, Bhatnagar A, Conklin DJ. Exposure to fine particulate air pollution causes vascular insulin resistance by inducing pulmonary oxidative stress. Environmental Health Perspectives. 2016; 124 (12):1830-1839 - 175.
Fisher-Hoch SP, Mathews CE, McCormick JB. Obesity, diabetes and pneumonia: The menacing interface of non-communicable and infectious diseases. Tropical Medicine & International Health. 2013; 18 (12):1510-1519 - 176.
Falagas ME, Kompoti M. Obesity and infection. Lancet Infectious Diseases. 2006; 6 (7): 438-446 - 177.
Baik I, Curhan GC, Rimm EB, Bendich A, Willett WC, Fawzi WW. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Archives of Internal Medicine. 2000; 160 (20):3082-3088 - 178.
Jedrychowski W, Maugeri U, Flak E, Mroz E, Bianchi I. Predisposition to acute respiratory infections among overweight preadolescent children: An epidemiologic study in Poland. Public Health. 1998; 112 (3):189-195 - 179.
Moore SI, Huffnagle GB, Chen GH, White ES, Mancuso P. Leptin modulates neutrophil phagocytosis of Klebsiella pneumoniae . Infection and Immunity. 2003;71 (7):4182-4185 - 180.
Mancuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW, Huffnagle GB. Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. Journal of Immunology. 2002; 168 (8):4018-4024 - 181.
Corrales-Medina VF, Valayam J, Serpa JA, Rueda AM, Musher DM. The obesity paradox in community-acquired bacterial pneumonia. International Journal of Infectious Diseases. 2011; 15 (1):e54-e57 - 182.
Salnikova LE, Smelaya TV, Moroz VV, Golubev AM, Rubanovich AV. Host genetic risk factors for community-acquired pneumonia. Gene. 2013; 518 (2):449-456 - 183.
Smelaya TV, Belopolskaya OB, Smirnova SV, Kuzovlev AN, Moroz VV, Golubev AM, et al. Genetic dissection of host immune response in pneumonia development and progression. Scientific Reports. 2016; 6 :35021 - 184.
Salnikova LE, Smelaya TV, Vesnina IN, Golubev AM, Moroz VV. Genetic susceptibility to nosocomial pneumonia, acute respiratory distress syndrome and poor outcome in patients at risk of critical illness. Inflammation. 2014; 37 (2):295-305 - 185.
Salnikova LE, Smelaya TV, Golubev AM, Rubanovich AV, Moroz VV. CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications. Molecular Biology Reports. 2013; 40 (11):6163-6176 - 186.
Salnikova LE, Smelaya TV, Moroz VV, Golubev AM, Rubanovich AV. Functional polymorphisms in the CYP1A1, ACE, and IL-6 genes contribute to susceptibility to community-acquired and nosocomial pneumonia. International Journal of Infectious Diseases. 2013; 17 (6):e433-e442 - 187.
Azab SF, Abdalhady MA, Elsaadany HF, Elkomi MA, Elhindawy EM, Sarhan DT, et al. Interleukin-10 -1082 G/A gene polymorphisms in Egyptian children with CAP: A case-control study. Medicine (Baltimore). 2016; 95 (26):e4013 - 188.
Zhao J, Zhang W, Shen L, Yang X, Liu Y, Gai Z. Association of the ACE, GSTM1, IL-6, NOS3, and CYP1A1 polymorphisms with susceptibility of Mycoplasma pneumoniae pneumonia in Chinese children. Medicine (Baltimore). 2017;96 (15):e6642 - 189.
Hayden LP, Cho MH, McDonald MN, Crapo JD, Beaty TH, Silverman EK, et al. Susceptibility to childhood pneumonia: A genome-wide analysis. American Journal of Respiratory Cell and Molecular Biology. 2017; 56 (1):20-28 - 190.
Chou SC, Ko HW, Lin YC. CRP/IL-6/IL-10 Single-nucleotide polymorphisms correlate with the susceptibility and severity of community-acquired pneumonia. Genetic Testing and Molecular Biomarkers. 2016; 20 (12):732-740 - 191.
Mao ZR, Zhang SL, Feng B. Association of IL-10 (−819 T/C, −592A/C and −1082A/G) and IL-6 -174G/C gene polymorphism and the risk of pneumonia-induced sepsis. Biomarkers. 2017; 22 (2):106-112 - 192.
Nascimento LF, Pereira LA, Braga AL, Módolo MC, Carvalho JA. Effects of air pollution on children's health in a city in Southeastern Brazil. Revista de Saúde Pública. 2006; 40 (1):77-82 - 193.
Arbex MA, Santos UeP, Martins LC, Saldiva PH, Pereira LA, Braga AL. Air pollution and the respiratory system. Jornal Brasileiro de Pneumologia. 2012; 38 (5):643-655 - 194.
Negrisoli J, Nascimento LF. Atmospheric pollutants and hospital admissions due to pneumonia in children. Revista Paulista de Pediatria. 2013; 31 (4):501-506 - 195.
Ehrlich R. Effect of nitrogen dioxide on resistance to respiratory infection. Bacteriological Reviews. 1966; 30 (3):604-614 - 196.
Jakab GJ. Modulation of pulmonary defense mechanisms against viral and bacterial infections by acute exposures to nitrogen dioxide. Research Report. Health Effects Institute. 1988;(20):1-38 - 197.
Rose RM, Fuglestad JM, Skornik WA, Hammer SM, Wolfthal SF, Beck BD, et al. The pathophysiology of enhanced susceptibility to murine cytomegalovirus respiratory infection during short-term exposure to 5 ppm nitrogen dioxide. American Review of Respiratory Diseases. 1988; 137 (4):912-917 - 198.
Rose RM, Pinkston P, Skornik WA. Altered susceptibility to viral respiratory infection during short-term exposure to nitrogen dioxide. Research Report. Health Effects Institute. 1989;(24):1-24 - 199.
Finnerty K, Choi JE, Lau A, Davis-Gorman G, Diven C, Seaver N, et al. Instillation of coarse ash particulate matter and lipopolysaccharide produces a systemic inflammatory response in mice. Journal of Toxicology and Environmental Health. Part A. 2007; 70 (23):1957-1966 - 200.
Lebowitz MD, Fairchild GA. The effects of sulfur dioxide and A2 influenza virus on pneumonia and weight reduction in mice: An analysis of stimulus-response relationships. Chemico-Biological Interactions. 1973; 7 (5):317-326 - 201.
Ameredes BT, Otterbein LE, Kohut LK, Gligonic AL, Calhoun WJ, Choi AM. Low-dose carbon monoxide reduces airway hyperresponsiveness in mice. American Journal of Physiology—Lung Cellular and Molecular Physiology. 2003; 285 (6):L1270-L1276 - 202.
Hollingsworth JW, Kleeberger SR, Foster WM. Ozone and pulmonary innate immunity. Proceedings of the American Thoracic Society. 2007; 4 (3):240-246