A micro-lung chip with macrophages for targeted anti-fibrotic therapy

Abstract Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. Macrophages are implicated in the fibrotic process, but exhibit remarkable plasticity in the activated immune environment in vivo, presenting significant challenges as therapeutic targets. To explore the influence of macrophages on IPF and develop macrophage-targeted therapies, we engineered a micro-lung chip with a lung epithelium-interstitium tissue unit to establish a controlled immune environment containing only macrophages. We discovered that macrophages exacerbated inflammation and fibrosis by comparing microchips treated with bleomycin in the presence and absence of macrophages. Based on the duration of bleomycin treatment, we established pathological models corresponding to inflammation and fibrosis stages. Transcriptome analysis revealed that activation of the PI3K-AKT signaling pathway facilitates the transition from inflammation to fibrosis. However, LY294002, a PI3K inhibitor, not only suppressed fibrosis and decreased the accumulation of M2 macrophages but also intensified the severity of inflammation. These findings suggest that macrophages play a pivotal role in the potential development at the tissue level. The micro-lung chip cocultured with macrophages holds significant potential for exploring the pathological progression of IPF and elucidating the mechanisms of anti-fibrotic drugs.