Idiopathic lung fibrosis (IPF) is a fatal disease that primarily affects the elderly. Up to date, the specific pathophysiology of IPF remains unknown. However, it is theorized to be caused by chronic repetitive injuries to the alveolar epithelium, eventually exhausting the stem cell capacity and activating pathological pathways. Heat shock proteins (HSPs), a category of stress response proteins, are also suggested to contribute to IPF pathophysiology. Furthermore, HSPs are key components in the regulation of cell homeostasis and act as chaperones for a multitude of new proteins. This review thoroughly evaluates the roles that specific HSPs, HSP90, HSP70, and HSP47, have in the fibrotic process. A close look into the roles of these HSPs in IPF pathophysiology will give valuable insight into the future of IPF treatment and prevention.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an inflammatory/transitional cell state in a PGF2α/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.