**5.1. Outdoor air pollution and lung health**

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

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.

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

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

**4.2. Effect of sex hormones in immune responses and lung development**

enhances pulmonary vascular remodeling [124].

currently under investigation.

14 Contemporary Topics of Pneumonia

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**.

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 (NO<sup>2</sup> ), carbon monoxide (CO), sulfur dioxide (SO<sup>2</sup> ), 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 NO<sup>2</sup> were two of the main air pollutants related to respiratory diseases, followed by PM10, PM2.5, O3, CO, and SO<sup>2</sup> . 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].

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

Understanding the Intersection of Environmental Pollution, Pneumonia, and Inflammation: Does...

Accumulating epidemiological, clinical, and experimental evidence suggests that exposure to air pollutants can have serious effects in metabolic and endocrine function, particularly in

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

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

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 proinflammatory 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

, tobacco

17

http://dx.doi.org/10.5772/intechopen.69627

glucose metabolism [159, 160]. Air pollution, especially traffic-related exposures, NO<sup>2</sup>

**5.2. Metabolic effects of air pollution and their relationship with pneumonia**

was associated with increased survival in patients hospitalized with CAP [181].

**5.3. Genetic contributions to pneumonia risk and severity**

toxicity for women due to increased internal exposure [158].

stress [174].

proteins [183].

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


**Table 4.** Common air pollutants and health effects.

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].

particulates (PM10), nitrogen dioxide (NO<sup>2</sup>

16 Contemporary Topics of Pneumonia

lution than other population groups [153, 156, 157].

**Pollutant Health effects**

Carbon monoxide

**Table 4.** Common air pollutants and health effects.

Ozone Decreased lung function

Particulate matter Decreased lung function

Nitrogen dioxide Increased airway reactivity

Sulfur dioxide Increased respiratory mortality

), carbon monoxide (CO), sulfur dioxide (SO<sup>2</sup>

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 NO<sup>2</sup>

air pollutants related to respiratory diseases, followed by PM10, PM2.5, O3, CO, and SO<sup>2</sup>

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 pol-

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

> Increased airway reactivity Increased lung inflammation

Increased respiratory symptoms

Increased mortality

Increased mortality

Reduced lung function Bronchitis (children)

Aggravation of lung disease Increased lung inflammation

Increased hospital visits for lung disease

Increased hospital visits for lung disease

), and

. Young

were two of the main

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, NO<sup>2</sup> , 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].
