Refractory Lung Diseases: From Cellular Structures, Molecular Mechanisms to Therapeutic Strategies

Refractory lung diseases (RLDs) encompass a spectrum of progressive pulmonary disorders, including acute respiratory distress syndrome (ARDS), bronchopulmonary dysplasia (BPD), and idiopathic pulmonary fibrosis (IPF). These conditions are defined by poor responsiveness to current therapeutic interventions and pose substantial clinical challenges, primarily due to their high morbidity and mortality rates. This review synthesizes the current understanding of the molecular mechanisms underlying RLDs and explores promising therapeutic strategies. A core feature of RLD pathogenesis is the disruption of alveolar microenvironmental homeostasis, which triggers a bidirectional vicious cycle between structural damage and disease progression. This homeostatic collapse is driven by interconnected pathological networks-including oxidative stress coupled with mitochondrial dysfunction, inflammatory immune dysregulation, and mechanical stress-induced extracellular matrix (ECM) remodeling-all of which are elaborated in this review. Collectively, these pathological processes contribute to therapeutic resistance. Based on these mechanistic insights, potential therapeutic approaches are discussed, such as antioxidant therapies (e.g., the mitochondria-targeted antioxidant Mitoquinone mesylate [MitoQ]) and antifibrotic agents (e.g., pirfenidone, nintedanib, as well as emerging strategies targeting Wnt pathway modulation). Additionally, the critical significance of early diagnosis and personalized precision medicine is emphasized. Future research should focus on a deeper characterization of the dynamic alterations within the alveolar microenvironment under pathological conditions, with the aim of developing more precise diagnostic tools and targeted therapeutic strategies. Ultimately, the therapeutic goal for RLDs should shift from mere symptom management to achieving pathological reversal.