Collagen crosslinking and organizational patterns reflect common disease processes in idiopathic pulmonary fibrosis and non-resolving acute respiratory distress syndrome

Rationale: Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and fibroproliferative remodeling in acute respiratory distress syndrome (ARDS), are characterized by increased extracellular matrix (ECM) deposition. However, measuring collagen accumulation alone does not capture differences in ECM organization or biochemical maturation that may distinguish persistent fibrosis from potentially reversible remodeling. Objectives: To examine collagen organization characteristics and mature (pyridinoline) collagen crosslinking amount in established end stage fibrotic lung disease (IPF) and fibroproliferation following an acutely damaged lung (non-resolving (NR) ARDS) and to investigate any relationships in these parameters and temporal tissue remodeling. Methods: Human lung tissue samples from control subjects, patients with IPF, and NR-ARDS were analyzed. Collagen amount and fiber organization were digitally quantified using picrosirius red staining. Mature collagen crosslinking was assessed by quantification of pyridinoline crosslinks. Measurements and Main Results: Lung tissue from both IPF and NR-ARDS lungs had higher collagen content compared with controls. Collagen fiber organization differed between groups. IPF lungs exhibited collagen architectures consistent with established fibrosis, whereas NR-ARDS lungs showed altered but less stabilized collagen organization despite similarly elevated collagen levels. Mature collagen crosslinks were significantly higher in IPF lungs but not in NR-ARDS lungs compared to controls. Integrated analyses identified distinct disease-associated ECM phenotypes, indicating that higher collagen abundance in NR-ARDS, unlike IPF, is not accompanied by more mature and persistent collagen crosslinking. Conclusions: Despite shared increases in collagen content, IPF and NR-ARDS lungs differ fundamentally in collagen organization and crosslinking maturity, suggesting differences in the reversibility of these conditions.