During lung development, it is known that the female fetal lung develops surfactant protein (SFTP) at an earlier time than the male lung, due to lack of androgen mediated decrease in SFTP [102]. The mechanism of this is believed due to chronic androgen exposure leading to an EGF-R mediated increase in TGF-β and subsequent decrease in SFTPB and SFTPC expression in type II alveolar epithelial cells (AECs) [103]. This phenomenon negatively regulates type II AEC maturation, with reverse cell reprogramming to a more immature cellular state [104]. Interestingly, an increase in production of SFTPA in those patients diagnosed with IPF portends a poor prognosis, with rapid decline in lung function, but this phenomenon is not recognized as being gender-specific [105].

Though several studies have examined the role of telomerase (TERT/TERC) mutation and subsequent telomere shortening in association with development of IPF, these studies have been for the most part sex matched and controlled, therefore rendering them difficult to glean information from regarding differences between men and women [106, 107]. Only one study has examined the role of sex hormones acting on the TERT gene [108]. This group began by noting that androgen therapy is often helpful in patients with disease of telomere dysfunction, such as dyskeratosis congenita. In this study, increased exposure of human cells from patients with telomerase dysfunction to estradiol correlated with increased telomerase activity and increased TERT mRNA production. Tamoxifen, an antagonist, caused the opposite effect, abolished by blocking signaling of estrogen receptor (ER)-A. It would thus be interesting to examine the finding in tissue provided by patients with IPF secondary to telomerase dysfunction, or even those with sporadic IPF .

Despite literature on correlation between MUC promoter regions and presence of IPF, little data exists on delineating the role of sex hormones in MUC-production or pathogenesis. The most relevant study examined decreased production of MUC2 in the gastrointestinal (GI) tract, showing a decreased response to GI injury in male versus female mice [109]. Whether this decrease, or alteration in function, exists in response to chronic lung injury, is unknown.

While a detailed description is beyond the scope of this chapter, in short the UPR is a method by which the cell has developed to handle misfolded proteins, either from genetic mutations (such as a change in SFTP), or viral infection [111]. It is an adaptive response to cell injury of most any type that halts production, or augments, of proteins to facilitate proper folding and functioning, with the aid of cellular chaperoning. An accumulation of misfolded proteins leads to the phenomenon of ER-stress, and apoptosis [112]. In IPF, increased ER-stress has been shown to be integral to fibrotic remodeling in type II AECs. Using mice with mutated, and misfolded, SFTPC in type II AECs, mice were given a “second hit” with intratracheal bleomycin, exposing the vulnerable epithelium to fibrotic remodeling [113].

No current literature is available that links UPR or ER-stress to gender-related development or progression of IPF, however a few studies are suggestive of a link. The first study showed that female mice were protected against development of insulin-resistance in inflammatory-cell associated obesity [114]. Though not mediated directly by ER-stress, the authors did show a decrease in UPR marker Gp78, suggesting that female sex was protective against progression of the UPR. In a similar fashion, dextrose-induced ER-stress and superoxide production was shown to be attenuated in vascular endothelial cells exposed to increased levels of estradiol [115]. These studies are provocative for pathogenic mechanisms and potential therapies, as detailed in the final section of the chapter .

Since AEC hypertrophy and phenotypic alteration to a “fibroblast-like” state is an important phenomenon believed to be involved in development of UIP and IPF [116], a large amount of literature has focused on the crosstalk between epithelial and mesenchymal cells, and the hotly debated topic of EMT [117]. Little has been studied in the way of EMT related to IPF and gender, however the cancer literature provides several potential provocative avenues for future research.

An example is the role of estrogen receptors in EMT. ER-β has been shown to be protective against tumor cells with EMT features (down-regulation of E-cadherin and nuclear β-catenin activation) [118]. The picture quickly becomes complicated though, with competing literature demonstrating that proliferation of tumor cells producing ER-α is correlated with an increase in mesenchymal markers [119]. This may, in part, explain why functional studies have shown worse outcome associated with EMT in females versus males. One example is a study examining podocyte injury in rats via EMT-related fibrogenesis – female rats displayed increase injury and nephrosis, compared to control males [120].

The interaction between alveolar macrophages and AECs in coordinating fibroblast recruitment and activation is an active area of research in the field of pulmonary fibrosis. Innate immune cell marker CCL2 has been implicated in the development of IPF, via an alteration of macrophage polarization to a pro-inflammatory phenotype [121]. Similarly, macrophage major mediator LPA and receptor LPAR1 have been shown to be necessary for the development of pulmonary fibrosis in animal models [122].

Extrapolating data again from inflammation-mediated obesity research, increased levels of macrophage activation marker MCP-1 were found in male versus female patients, resulting in increased pancreatic islet cell destruction and fibrosis, and subsequent insulin resistance [123]. A similar phenomenon may be protect female versus male patients with pulmonary fibrosis, thought more studies are needed to explore this hypothesis fully .

The physiologic process that accompanies and coordinates wound repair is known to be deranged in fibroblasts isolated from patients with IPF. Normally cell-to-cell communicating proteins, called integrins, coordinate repair through interaction with the extracellular matrix (ECM) and effecter inflammatory cells such as circulating monocytes [124]. However, this feedback mechanism that prevents aberrant wound repair is often turned off in IPF patient samples [125].

Again, while no literature exists on alteration in integrin signaling and gender together influencing the development of pulmonary fibrosis, an association can be extrapolated from existing data. For example, one study has previously demonstrated increased integrin receptor signaling on circulating antigen presenting cells (APCs) after injury in men versus women [126]. Somewhat contradicting this concept is the finding that downstream pro-fibrotic mediators have been found to result in worsened lung fibrosis in estradiol-supplemented rats, in a bleomycin-model of pulmonary fibrosis [127]. Specifically, these investigators found increased transcriptional levels of procollagen I and TGF-β1—these levels were subsequently decreased after ovariectomy in similarly treated rats. However, other similar studies have drawn the polar opposite conclusion [128], suggesting that the true link is more complicated than appears and requires further study .

Thus, a large number of endogenous factors have a known and potentially enormous effect on the development of IPF in women, as well as men. However this is not the only influence on disease pathogenesis. For the remainder of this chapter, focus will be shifted from the effect of host factors in the development of IPF, to the influence of environment on disease pathogenesis. According to the most recent Centers for Disease Control and Prevention survey collected in 2012, over 42 million people currently smoke tobacco-related products in the United States alone, accounting for greater than 18 % of adults greater than 18 years of age (www.​cdc.​gov/​tobacco). Though overall prevalence has decreased from 2005 (20.9 % of adults at that time), tobacco-related death is estimated to account for over 400,000 deaths per year, or more than one out of every five recorded deaths (http://​www.​cdc.​gov/​mmwr/​index2014.​html). While men continue to be more likely to smoke than women (20.5 % versus 15.8 % of polled Americans), there is evidence that women are increasing their tobacco consumption worldwide, with an increase to 20 % of all women estimated by 2025 (approximately 530 million women) (http://​www.​cdc.​gov/​brfss/​annual_​data/​annual_​2013.​html). Most alarming is that despite inroads being made in anti-tobacco efforts in adolescent boys, there is a plateau seen in young women from 2005 to 2012, with evidence for increased use of cigarettes as casual smokers and an increased designation as a current daily smoker (18 % of girls versus 12 % of boys) (http://​www.​cdc.​gov/​nchs/​products/​nhsr.​htm). This is evidenced by an increased use of smoking on at least 20 days of the month (8 %, versus 6 % of young men). This trend is especially sustained in women with low income, represented by a minority group, and those who have a lower level of education .

Though the exact nature of the relationship between tobacco smoke and IPF is controversial, cigarette use is a known and validated risk factor for development and progression of IPF, with a near linear relationship described between amount of lifetime tobacco smoke exposure and decreased survival after diagnosis of IPF [143]. This increase in mortality is especially true as related to the relatively novel recognized entity of combined pulmonary fibrosis and emphysema (CPFE), which has an even worse prognosis than that described with isolated interstitial lung disease (less than 20 % survival at 2 years), and a four to five-fold increase in developing co-morbid pulmonary hypertension associated with chronic lung disease [144]. While the majority of patients with CPFE represented in the literature have been elderly men, there is an increasing incidence of women noted.

Familial and idiopathic IPF are known to have increased prevalence among ever-smokers, as evidenced by a study that showed an increase in disease development from 34.1 % to 67.3 % (p < 0.0001) with history of smoking [96]. However, it is worth noting that this estimate is at odds with data from an older study that showed better prognosis in patients diagnosed with IPF who were current smokers [145], though the article notes that the effect may have been influenced by smokers seeking earlier medical care than non-smokers. The latter point was supported by another study that showed better survival in non-smokers, with a noted “healthy smoker effect” (selection and survival bias intrinsic to previous trials study designs) leading to appearance of improved survival in smokers [146].

There exist biologically plausible mechanisms by which tobacco smoke may influence the development of IPF, strengthening the above correlations. The most thoroughly described mechanism involves cigarette-smoke induced oxidative stress that impairs the function of histone deacetylase (HDAC)-2 activity, contributing to post-translational modification of inflammatory gene regulators, leading to an increase in the chronic inflammatory state, and eventual fibrosis [147–149]. This line of research, and thus dedicated therapeutics targeting the described pathways, are still in their infancy. Thus, tobacco cessation remains the most heavily recommended treatment and prevention strategy .

There exist many hurdles to tobacco cessation that are unique to women. A major concern documented since the latter days of the women’s liberation movement has been the increased use of tobacco amongst women [150]. A concern from the late 1960s forward was that the appropriate equalization of rights between men and women in the work place and beyond would have an untoward side effect of equalizing use of products such as alcohol and cigarettes [151]. Advertising companies recognized this trend early, utilizing magazine and television advertisements to equate cigarette smoking with social attractiveness and stressing the utility of smoking to maintain low weight to female viewers [152]. This trend occurred in tandem with the pervasive thought that cigarette use represented a wholesome/healthy outdoor activity and was a status symbol representing increased free time and media exposure [153]. Television and print ads also began to successfully target households in a lower socioeconomic class, with an increase in tobacco use noted in such households since the early 1990s [154]. Such exposure focused on the notion of cigarette use for young women as liberating, sophisticated, attractive, glamorous and – importantly – slim [155]. However, there was also an elegant campaign directed at older women as well, focusing on the pleasurable aspects of cigarette use, stressing tobacco’s role in relaxation from day-to-day responsibilities and burdens [156].

Beyond sociologic influences on a woman’s hindrance to tobacco cessation, there exist biologic mechanisms that have been hypothesized to influence continued cigarette use. In its simplest form, the menstrual cycle itself has been found to influence smoking behavior [157], with an association found between the luteal phase of menstruation and increased craving for tobacco, ultimately, cigarette use [158]. In previously published survey data, women described a greater relief of “negative feelings” associated with the intake of nicotine, though subsequent studies have shown this correlation to be weak or nonexistent [159]. However, at least one study demonstrated that progesterone treatment in the early follicular phase of the menstrual cycle can attenuate cravings, and aid in tobacco cessation attempts [160].

From a similar pharmacologic standpoint, estrogen has also been shown to have an effect on cigarette smoking behavior. Estrogen supplementation, either through an oral contraceptive pill or pregnancy, may act as a non-competitive nicotine receptor antagonist leading to an alteration in nicotine pharmacokinetics, rendering a decrease in nicotine “effectiveness” and a need to smoke more cigarettes to achieve the same neuropsychological effects [161–163]. This phenomenon has been demonstrated in a rat model of tobacco use, where the female animal was more likely to self-administer nicotine during the estrogen peak of the estrous cycle [164].

The effect of progesterone and estrogen on addiction may partially explain why women require a shorter duration of exposure to nicotine in tobacco smoke in order to become addicted [165], though some of this effect may be due to susceptibility to external cues. The consideration of the effect of psychological disease similarly must be considered—patients with untreated depression and anxiety, of which women make up a majority, have increased use of tobacco products compared to treated control patients [166].

While metal, silica, and wood dust are consistently identified environmental risk factors for development of IPF in jobs historically conducted solely by men (shipbuilding, car manufacturing and furniture building) [167, 168], women do have independent known exposures that contribute to development and progression of pulmonary fibrosis. For example, in one study, women who practiced the profession of hairdressing were noted to have an increased odds ratio of development of IPF (3.6, 95 % CI 0.9–13.9), presumably secondary to exposure to noxious inhalants [169]. In addition, rural work exposure to vegetable and animal dust is noted to be a risk factor for development of pulmonary fibrosis in women, greater than men [170]. Importantly, this domiciliary exposure also extends to wood fire exposure, even in developed countries [171].

The vast majority of wood, or biomass, fuel exposure in women occurs globally, where it remains the most commonly used means of cooking and preparing food [172, 173]. Though some would argue that the lung disease that develops in response to this exposure is independent from a diagnosis of IPF—most categorizing the illness as a pneumoconiosis or hypersensitivity pneumonitis—the risk factor can cause a progressive chronic lung disease marked respiratory failure and development of cor pulmonale, at least similar to IPF [174, 175]. While the disease has been alternately referred to within the past several years as “hut lung” (a mixed-dust pneumoconiosis) in the literature [176], there exists reasonable evidence from studies that the exploration of occupational exposures, such as biomass fuel and food preparation remains a problem even outside of rural and underdeveloped areas. However, there is controversy regarding the occupational distribution that begs for larger and longer duration observational trials [177].