Predisposition for Disrepair in the Aged Lung

Abstract

Introduction Idiopathic pulmonary fibrosis (IPF) is a devastating progressive lung disease with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of IPF are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of IPF is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. Methods Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 (TGF-β1) production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. Results The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A (Fn-EDA) and the matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-β receptor 1 and TGF-β1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation. Conclusion Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-β1 expression and signaling and are populated by Thy-1–negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.

Mechanisms of Lung Fibrosis Resolution

“…Compared with young mice, fibroblasts isolated from aged mice show reduced Thy-1 expression, increased TGF-b receptor levels, increased expression of matrix proteins when incubated with TGF-b, and a higher resistance to apoptosis. 86,88,90 Senescent lung fibroblasts have been reported to resist apoptosis through the epigenetic mechanism of histone modification, resulting in up-regulation of the antiapoptotic gene, Bcl-2, and low expression of the proapoptotic gene, Bax. 91 Although the aged lung is more susceptible to the onset of fibrosis, few studies in the lung or other organs specifically address the capacity for resolution of established fibrosis in aged models.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Senescence, mitochondrial dysfunction, and insufficient autophagy in the aging lung might have implications in maladaptive responses to stress. For instance, elderly mice are more vulnerable to fibrosis after injury or stress (17,21,22) and have a lower capacity for normal repair after damage (23). In this context, our group has shown that the lung's protective mechanisms against injury, such as mesenchymal stem cell differentiation, are also impaired with age (24).…”

The role of a7 nicotine acetylcholine receptors in lung injury and repair.

“…Elements of transitional remodeling have also been demonstrated in alcoholexposed rats and mice [29,61], and in alcoholic subjects [68], in post-lung transplant recipients [69], and in aging mice [26]. However, the implications of transitional remodeling are unknown.…”

“…In the injured lung, fibronectin is deposited over denuded basement membranes where it is thought to support the migration of alveolar epithelial cells during repair [25]. The excessive deposition of fibronectin, however, has been hypothesized to promote disrepair [26]. Human studies also show increased fibronectin content within the bronchoalveolar lavage fluid of smokers [27].…”

“…In contrast, persistence of the transitional matrix may lead to ineffective repair after injury through the induction of pro-inflammatory agents directly or via the release of matrix fragments [70]. We and others have suggested that these changes may explain the increased incidence and mortality observed for acute lung injury in alcoholics [61,68], the predisposition to lung cancer in smokers [19,71], the development of rejection after lung transplantation [69], and the worse outcomes observed in elderly patients with pulmonary disorders [26]. However, until further studies are performed, these statements remain highly speculative.…”