Pulmonary fibrosis is an age-related condition. Good evidence connects it to the burden of senescent cells in the aging lung, but its causes are otherwise relatively poorly understood. Therapeutic options remain poor, and the prognosis for patients is quite ugly. Fibrosis is nanoscale scarring, an inappropriate buildup of excess extracellular matrix that is disruptive to tissue function. Researchers here explore a loss of the capacity of fibroblast cells to degrade extracellular matrix structures in aged tissue, and identify a regulatory gene that can be overexpressed to produce a greater defense against fibrosis in aged mice.
Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease whose incidence and severity increase markedly with age, indicating that aging is a primary risk factor for IPF. A study in murine models demonstrated that while bleomycin-induced pulmonary fibrosis (PF) can resolve spontaneously in young mice, this reparative capacity is significantly impaired in older animals, potentially causing persistent fibrosis.
A key mechanism underlying extracellular matrix (ECM) degradation involves the phagocytosis of collagen fibrils by fibroblasts and macrophages and their subsequent lysosomal degradation. Aging has been shown to impair the capacity of lung fibroblasts to degrade collagen independently of matrix metalloproteinase activity. Therefore, we hypothesized that an age-associated decline in collagen phagocytosis by fibroblasts is linked to lysosomal dysfunction. However, the upstream regulators governing this process remain poorly defined.
In vivo, aged mice showed impaired fibrosis resolution and reduced lung fPRDM16 levels. Fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mitochondrial reactive oxygen species (mitoROS). Enhancing lysosomal function with rapamycin or scavenging mitoROS with mitoquinone restored phagocytosis. fPRDM16 expression was downregulated with age and upon transforming growth factor-β (TGF-β) stimulation. Its overexpression rescued phagocytic defects, improved lysosomal acidification, and reduced mitoROS, thereby disrupting a pathogenic mitochondria-lysosome feedback loop.
We conclude that fPRDM16 downregulation in aging impairs fibroblast-mediated collagen clearance via a mitochondria-lysosome dysfunction loop. Targeting fPRDM16 may represent a novel therapeutic strategy to promote fibrosis resolution.
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