A Self-Sustaining Repair Circuit Drives the Progression of Pulmonary Fibrosis.

Authors

Duc-Hiep Bach, Trung Kien Nguyen, Hai Pham-The, Thanh Liem Nguyen

Published in

Translational research : the journal of laboratory and clinical medicine. Aug 01, 2026. Epub Aug 01, 2026.

Abstract

Pulmonary fibrosis is a progressive and often fatal lung disorder whose clinical behavior is not fully explained by conventional injury-driven models. Fibrosis frequently progresses after the initiating insult has resolved, anti-inflammatory therapies have shown limited benefit in idiopathic pulmonary fibrosis, and current antifibrotic drugs slow but rarely reverse disease progression. Moreover, diverse conditions including idiopathic pulmonary fibrosis, post-ARDS or post-infectious fibrosis, radiation-induced injury, drug toxicity, and bronchopulmonary dysplasia arise from distinct causes yet may converge toward shared features of persistent fibrotic remodeling. Here we propose that pulmonary fibrosis represents a self-sustaining pathological tissue-repair state rather than a continuously injury-dependent process. Failure of alveolar epithelial regeneration produces persistent cellular senescence and chronic distress signaling that recruits reparative immune responses. These signals promote fibroblast survival and myofibroblast persistence, leading to extracellular matrix deposition and progressive tissue stiffening. Increased matrix stiffness further disrupts epithelial recovery through mechanotransduction pathways, creating a feedback loop linking epithelial dysfunction, immune mis-repair, stromal stabilization, and mechanical reinforcement. Within this framework, fibrosis persists because the lung behaves as a chronically unhealed wound. This model may help explain disease progression and heterogeneity and suggests that effective therapies must restore epithelial regeneration and disrupt system-level feedback rather than target single profibrotic pathways.

PMID:
42542182
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

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