Sexual Dimorphism in Interstitial Lung Disease

Abstract

Interstitial lung diseases (ILD) are a group of heterogeneous progressive pulmonary disorders, characterised by tissue remodelling and/or fibrotic scarring of the lung parenchyma. ILD patients experience lung function decline with progressive symptoms, poor response to treatment, reduced quality of life and high mortality. ILD can be idiopathic or associated with systemic or connective tissue diseases (CTD) but idiopathic pulmonary fibrosis (IPF) is the most common form. While IPF has a male predominance, women are affected more greatly by CTD and therefore associated ILDs. The mechanisms behind biological sex differences in these progressive lung diseases remain unclear. However, differences in environmental exposures, variable expression of X-chromosome related inflammatory genes and sex hormones play a role. Here, we will outline sex-related differences in the incidence, progression and mechanisms of action of these diseases and discuss existing and novel cellular and pre-clinical studies. Furthermore, we will highlight how sex-differences are not adequately considered in pre-clinical disease models, how gender bias exists in clinical diagnosis and how women are underrepresented in clinical trials. Future action on these observations will hopefully shed light on the role of biological sex in disease development, identify potential targets for intervention and increase female participant numbers in clinical trials.

Keywords: X-chromosome; connective tissue diseases; gender differences; idiopathic pulmonary fibrosis; interstitial lung diseases; sex hormones; sexual dimorphism.

Figure 1

Schematic view of the pathogenesis of pulmonary fibrosis. Genetic and epigenetic factors in combination with repeated injury from environmental factors to the lung alveolar epithelium result in epithelial and endothelial cell damage and the disruption of the basement membrane. This initiates an inflammatory response and the secretion of pro-fibrotic cytokines such as TGF-β, PDGF, VEGF, IL-4 and IL-13. This results in the activation of the coagulation cascade, abnormal vascular remodelling and repair and aberrant epithelial-mesenchymal crosstalk, together with the recruitment, migration and differentiation of fibroblasts/fibrocytes into myofibroblasts. These myofibroblasts are resistant to apoptosis and accumulate, resulting in extracellular matrix deposition and the formation of fibrotic lesions, which leads to progressive lung remodelling and architectural distortion. TGF-β = transforming growth factor beta; PDGF = platelet-derived growth factor; VEGF = vascular endothelial growth factor; IL-4 = interleukin 4; IL-13 = interleukin 13. Created with BioRender.com.