Endothelial–Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis

Abstract

The pathological hallmark lesions in idiopathic pulmonary fibrosis are the fibroblastic foci, in which fibroblasts are thought to be involved in the tissue remodeling, matrix deposition, and cross-talk with alveolar epithelium. Recent evidence indicates that some fibroblasts in fibrosis may be derived from bone marrow progenitors as well as from epithelial cells through epithelial-mesenchymal transition. To evaluate whether endothelial cells could represent an additional source for fibroblasts, bleomycin-induced lung fibrosis was established in Tie2-Cre/CAG-CAT-LacZ double-transgenic mice, in which LacZ was stably expressed in pan-endothelial cells. Combined X-gal staining and immunocytochemical staining for type I collagen and a-smooth muscle actin revealed the presence of X-galpositive cells in lung fibroblast cultures from bleomycin-treated mice. To explore the underlying mechanisms, by which loss of endothelial-specific markers and gain of mesenchymal phenotypes could be involved in microvascular endothelial cells, the effects of activated Ras and TGF-b on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-b caused a significant loss of endothelial-specific markers, while inducing de novo mesenchymal phenotypes. The altered expression of these markers in MS1 cells with activated Ras persisted after withdrawal of TGF-b in vitro and in vivo. These findings are the first to show that lung capillary endothelial cells could give rise to significant numbers of fibroblasts through an endothelial-mesenchymal transition in bleomycin-induced lung fibrosis model.

Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury

“…The direct treatment of endothelial cells with BLM in vitro has been shown to induce the secretion of certain profibrotic mediators (7,8), but little is known about the effects of BLM on endothelial cells in vivo. Moreover, recent studies have suggested that a process known as the endothelial-to-mesenchymal transition (EndMT) may be activated during fibrotic processes, creating fibroblast-like cells that contribute to excess collagen production (8,9). Finally, the activation of endothelial cells may contribute to prolonged tissue injury by promoting a proinflammatory environment.…”

The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

“…In SSc, targeting of the TGF␤-dependent EndoMT process via small-molecule kinase inhibitors, such as imatinib mesylate and rottlerin, might represent a promising treatment for both tissue fibrosis and vasculopathy, the two major aspects of the disease. Indeed, EndoMT might substantially contribute not only to pathologic vascular remodeling in SSc, but also to dermal and internal organ fibrosis, as has recently been observed in experimental models of kidney and lung fibrosis (13,15). Previous studies have shown that blocking of c-Abl with imatinib mesylate could prevent, or induce regression of, dermal fibrosis in different mouse models of SSc and could attenuate bleomycin-induced pulmonary fibrosis in mice (24)(25)(26).…”

“…EndoMT is a phenomenon that is reported to occur during embryonic cardiovascular development and also is reported to play an important role during several pathologic conditions, including cardiac, pulmonary, and renal fibrosis, carcinoma-associated interstitial fibrosis, and vascular pathologies (9,(11)(12)(13)(14)(15)(16). Indeed, recent evidence has shown that a substantial proportion of myofibroblasts arise from ECs via EndoMT in experimental renal fibrosis and bleomycin-induced pulmonary fibrosis in mice (13,15).…”

“…Indeed, recent evidence has shown that a substantial proportion of myofibroblasts arise from ECs via EndoMT in experimental renal fibrosis and bleomycin-induced pulmonary fibrosis in mice (13,15). A possible role of EndoMT in the neointimal thickening observed in transplant atherosclerosis and restenosis has also been suggested (11).…”

Osteoplastic pneumopathy as epithelial-mesenchymal transformation and pneumoconiosis (analytical review and own observations)

“…Констатация сочетания фиброза и кальцифика ции, понятная лишь с позиций гистогенетической общности мезенхимальных предшественников со единительной и костной тканей, изменилась в конце 1990 х годов при выявлении биохимических и моле кулярных звеньев патогенеза фиброзирующих и ос сифицирующих заболеваний в целом [29][30][31], в т. ч. и системы органов дыхания [11,[32][33][34], а также таких клинически значимых заболеваний, как ге теротопическая оссификация у обездвиженных па циентов с ожогами, обширными травмами скелета, черепно мозговыми или спинальными травма ми [35][36][37] и прогрессирующая оссифицирущая фибродисплазия [38][39][40]. С этого времени в патоге нетический каскад стали включаться про и проти вовоспалительные, ростовые факторы и рецепторы к ним, молекулы адгезии, сигнальной трансдукции, регуляторы трансляции (активирующие и ингибиру ющие).…”