Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male-female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-beta (TGF-beta) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-beta and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.

Automated summary

In mouse models of chemically induced chronic lung injury and pulmonary fibrosis, female mice exhibited higher survival rates, less weight loss, lower levels of white blood cells and total protein content, less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores compared to male mice. Females also showed reduced activation of transforming growth factor-beta and downstream signaling pathways, suggesting a protective mechanism against chronic complications of lung injury.