抄録
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by excessive collagen deposition and irreversible scarring. Reliable animal models are essential for elucidating IPF pathogenesis and evaluating antifibrotic therapies. However, conventional bleomycin (BLM) models generally induce only transient and moderate fibrosis. Considering the profibrotic role of eosinophils, we developed a novel IPF model using the spontaneous eosinophilic mutant Yama mice strain to achieve persistent and severe fibrosis. Male Yama and C57BL/6 mice (6 weeks old, n = 24) received eight intranasal administrations of BLM (2 mg/kg) at two-week intervals, while controls received saline. Peripheral eosinophil counts were monitored, and tissues were analyzed histologically and biochemically. Yama mice exhibited a sharp eosinophil peak after the first BLM exposure, followed by a gradual decline. Histological analysis revealed markedly enhanced fibrosis, greater collagen deposition, and higher Ashcroft scores in Yama mice than in C57BL/6 mice. Alcian blue–PAS-positive fibroblast foci, a characteristic feature of human IPF, were abundant in Yama mice. Immunohistochemistry demonstrated increased expression of eosinophil cationic protein (ECP). Moreover, mRNA expression of Th2 cytokines (IL-4, IL-5, IL-13) and profibrotic mediators (IL-6, Col1a1) was significantly higher in Yama mice. However, the pronounced fibrotic changes, TGF-β expression exhibited only a modest increase in Yama mice, suggesting that fibrosis might develop via pathways not totally dependent on conventional TGF-β signaling. This repeated BLM administration model successfully reproduces the key pathological features of severe IPF and emphasizes the pivotal contribution of eosinophils to fibrogenesis.
