Abstract
Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by significant extracellular matrix (ECM) accumulation and persistent scarring of lung tissues. Despite improvements in understanding its pathophysiology, effective therapeutic options are limited. Increasing evidence pertains to the critical importance of macrophages, which are major regulators of innate immunity and demonstrate remarkable plasticity that determines PF development. Classically activated M1 macrophages promote pro-inflammatory responses, whereas alternatively activated M2 macrophages facilitate tissue repair and remodelling. In fibrotic lungs, a chronic bias toward M2 phenotypes promotes fibroblast activation, collagen accumulation, and abnormal wound repair. Additionally, macrophage polarization is very dynamic, influenced by cytokines, growth factors, metabolic reprogramming, and epigenetic regulation in the microenvironment. This dynamic flexibility highlights their dual role; protective during acute damage and harmful in chronic fibrosis. Recent research suggests that addressing transcriptional networks and metabolic checkpoints that control macrophage fate can regulate inflammatory and fibrotic responses. Therapeutic approaches targeted at reprogramming macrophages to an M1 phenotype show promise for attenuating or halting fibrotic development. This review underlines the importance of macrophage polarization plasticity in PF, focusing on its dualistic nature and the molecular mechanisms that regulate phenotypic switching. It emphasizes macrophage flexibility as a major area for intervention by combining current insights into macrophage biology with developing treatment approaches, combining innate immune regulation with fibrotic remodelling and highlighting potential strategies to support the restoration of lung homeostasis.