Fig. 4: Hypothesized profibrotic disease mechanism by which hematopoietic Y loss in men might exacerbate IPF.

We propose an exacerbation of pulmonary fibrosis in male IPF patients with mLOY by activation of established profibrotic pathways. First, circulating LOY-monocytes infiltrate lung tissues and differentiate into pulmonary LOY-macrophages. Next, increased TGF-β1 signaling in LOY-macrophages upregulates FN1 and SPP1 expression. Following this, myofibroblast differentiation is stimulated by enhanced FN1-mediated interaction between LOY-macrophages and lung fibroblasts. Myofibroblasts are known for excessive secretion of extracellular matrix (ECM) components such as proteoglycans, collagens, and fibronectins.