Nerandomilast attenuates Pantoea agglomerans-induced hypersensitivity pneumonitis by regulating M1 macrophage polarization and fibroblast activation

Hypersensitivity pneumonitis (HP) is characterized by bronchiolocentric inflammation and fibrosis. The characteristic pathological features include bronchiolocentric inflammation, peribronchiolar fibrosis, and the presence of poorly formed granulomas. Nerandomilast is a novel oral phosphodiesterase 4 (PDE4) inhibitor with good selectivity for PDE4B. PDE4 inhibitors (PDE4i) exhibit anti-inflammatory/antifibrotic properties, the efficacy of nerandomilast remains unexplored in HP. We selected macrophages and fibroblasts as effector cells for the inflammatory and fibrotic phases of HP in vitro. And we established in vivo HP models induced by saline extract of the cells of P. agglomerans (SE-PA). The results of the in vitro studies revealed that nerandomilast inhibited the expression of proinflammatory markers (i.e., CD86, iNOS, and IL-1β) of M1 macrophages by increasing CREB phosphorylation and inhibiting the NF-κB signaling pathway. Furthermore, nerandomilast reduced TGFβ1-induced fibroblast activation by inhibiting Smad and non-Smad signaling pathways. In vivo studies confirmed that nerandomilast could reduce the number of inflammatory cells in bronchoalveolar lavage fluid and the secretion of proinflammatory cytokines (such as IL-1β, IL-6, and TNF-α), lower the serum levels of the oxidative stress markers MPO and MDA, and inhibit the transcription of proinflammatory cytokines in lung tissue. Moreover, nerandomilast alleviated pulmonary fibrosis and pulmonary dysfunction in mice with HP induced by SE-PA. Our findings indicated that nerandomilast might attenuate inflammation and fibrosis in SE-PA-induced HP mice by regulating macrophage polarization and inhibiting fibroblast activation, which provides new insights for the clinical treatment of HP.