Cellular senescence is now well recognized as an important contributing cause of fibrosis, a malfunction of normal tissue maintenance that involves deposition of excess collagen into scar-like structures that degrade tissue function. Pulmonary fibrosis is one of the better studied age-related fibrotic conditions, and over the past decade it has been increasingly linked to cellular senescence. Some of the first clinical trials of senolytic drugs to clear senescent cells, using the dasatinib and quercetin combination, were carried out in patients with idiopathic pulmonary fibrosis.
Senescent cells cause harms, such as the disruption of regenerative processes that leads to fibrosis, via the signals that they generate, the pro-inflammatory, pro-growth senescence-associated secretory phenotype (SASP). How exactly does the SASP produce fibrosis, however? Today's open access paper is an example of the research initiatives presently attempting to answer that question. The focus here is on the production of excess fibroblasts, cells that produce the collagen structures of the extracellular matrix, in the context of fibrosis, and the mechanisms by which this happens.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT).
Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT.
Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.