Mechanical properties and mechanobiology of lung collagen fibers
Embargo Date
2028-02-05
OA Version
Citation
Abstract
Collagen fibers are one of the key load-bearing components of lung tissue. The development, maintenance, and remodeling of collagen require collagen-related enzymes whose dysregulated release and activity can lead to the pathogenesis and progression of diseases. Emphysema, an important component of chronic obstructive pulmonary disease (COPD), is an uncurable lung disease, characterized by fiber failure and alveolar enlargement. During lung inflation, collagen fibers are stretched and generate gradually increasing recoil forces as wavy fibrils in the fibers become straight, protecting cells and soft tissue from mechanical failure. As a result of tissue remodeling, COPD progression may be accompanied with compromised fiber structure and mechanical function. Additionally, neutrophils, the first immune responders, mediate rapid inflammation, which intensifies during COPD exacerbations that are triggered by infection or injury. We hypothesized that compromised collagen fiber structure and mechanics, combined with increased neutrophil activity caused by emphysema-associated agents such as cigarette smoke or secreted collagenases contribute to emphysema progression, potentially via a positive-feedback loop. To test this hypothesis, single collagen fibers were first isolated from bovine lung tissue and their mechanical properties were measured during bacterial collagenase degradation under physiological mechanical forces. Collagen fibers were then isolated from human precision-cut lung slices (hPCLS) obtained from healthy and COPD donors. The mechanical properties of these fibers were also measured. Computational modeling was applied to the fiber data to estimate the effective mechanical properties fibrils. Next, the extracellular matrix (ECM) structure and mechanics of hPCLS from healthy and diseased donors were analyzed. Finally, neutrophil response to ECM structure and emphysema-associated agents were studied by visualizing and quantifying neutrophil migration in mouse PCLS (mPCLS).
The results showed that physiological mechanical forces accelerate the degradation of lung collagen fibers. Computational modeling allowed the estimation of fibril stiffness and demonstrated that collagenase weakens individual fibrils which in turn increases the risk of fibril rupture. Human collagen fibers from COPD donors tended to be softer than from healthy donors especially at lower strains. Recruitment of wavy fibrils was also delayed in the COPD fibers compromising their ability to protect the tissue. Neutrophils were found to migrate at a higher speed in collapsed than stretched regions of a lung that had been infected by lipopolysaccharide. Cigarette smoke and collagenase treatment of the mPCLS also increased migration speed. These effects were mitigated by inhibiting the cellular contractile apparatus and stretch-sensitive ion channels. Since collagen fiber rupture leads to alveolar airspace enlargement, the tissue surrounding the rupture site collapses which may activate neutrophils. In conclusion, the mechanisms uncovered in this work reveal how the mechanical properties and the mechanobiology of lung collagen fibers contribute to COPD progression.
Description
2026
License
Attribution 4.0 International