Abstract Rationale Idiopathic pulmonary fibrosis (IPF) exhibits a strong male predominance, with men experiencing more rapid disease progression and poorer outcomes than women. This clinical pattern suggests sex-specific biological drivers in IPF, yet the basis for this disparity remains poorly defined. Persistent fibroblast activation and chronic inflammation in IPF engage alveolar macrophages, which further promote fibrotic progression. However, whether sex influences macrophage activation and polarization states during lung fibrosis remains unknown. We therefore aimed to define sex-specific macrophage programs to uncover mechanisms underlying this disparity and identify potential therapeutic targets. Methods Male and female mice were challenged with bleomycin to induce pulmonary fibrosis. Bronchoalveolar lavage was performed at 0-, 7-, 14-, and 21-day post-challenge to isolate alveolar macrophages for bulk RNA sequencing. In parallel, lung tissues were collected for histological assessment of fibrotic pathology. Results Male mice exposed to bleomycin demonstrated increased inflammation and fibrosis by Day 14 and developed more severe fibrosis than females by Day 21, with greater collagen deposition and architectural distortion on histologic analysis. Across early timepoints (Days 0, 7, and 14), macrophages showed minimal sex-associated transcriptional differences. In contrast, at Day 21, when fibrosis peaked, male macrophages displayed a pronounced shift in transcriptional profiling, with 3,155 differentially expressed genes relative to female macrophages. Gene Ontology analysis revealed upregulation of interferon-beta signaling, immune regulatory pathways, and cytokine production in male macrophages, whereas pathways involved in ribosome biogenesis, RNA processing, and mRNA metabolism were significantly downregulated. Conclusion Consistent with clinical observations, the bleomycin mouse model recapitulated a male-biased fibrotic phenotype. Transcriptomic profiling at peak fibrosis identified that male macrophages undergo a robust interferon-driven immune activation coupled with global suppression of RNA metabolic and translational pathways. This transcriptional remodeling indicates a stress-adaptive immune state that prioritizes defense signaling over biosynthetic activity, potentially contributing to the heightened fibrotic response in males. This abstract is funded by: NIH/NHLBI R01HL146802; NIH/NHLBI T32HL007013; California UCOP TRDRP T32IR5347
Xu et al. (2026) studied this question.