Metformin reverses established lung fibrosis in a bleomycin model

Abstract

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs. Cellular metabolism regulates tissue repair and remodelling responses to injury. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…However, due to the lack of effective therapeutic drugs, tissue fibrosis still threatens human health. Although some drugs exhibit antifibrotic effects, including angiotensin‐converting enzyme inhibitors, aldosterone inhibitors, statins, angiotensin II type 1 receptor blockers, endothelin receptors, β‐blockers, acetylsalicylic acid, and matrix metalloproteinase (MMP) inhibitors, none of them are specifically designed to target fibrosis, and the related side effects limit their clinical use for treating fibrosis . Thus, antifibrotic and anticancer treatments are extremely urgent, and new therapeutic drugs should be designed based on specific targets that contribute to the progression of fibrosis and tumors.…”

“…Although some drugs exhibit antifibrotic effects, including angiotensinconverting enzyme inhibitors, aldosterone inhibitors, statins, angiotensin II type 1 receptor blockers, endothelin receptors, β-blockers, acetylsalicylic acid, and matrix metalloproteinase (MMP) inhibitors, none of them are specifically designed to target fibrosis, and the related side effects limit their clinical use for treating fibrosis. [3][4][5][6] Thus, antifibrotic and anticancer treatments are extremely urgent, and new therapeutic drugs should be designed based on specific targets that contribute to the progression of fibrosis and tumors.Epithelial-mesenchymal transition (EMT) is a reversible terminal differentiation process in which epithelial cells shed their properties and acquire a more mesenchymal phenotype. 7 EMT is a fundamental process widely involved in the development and the progression of various diseases, and there are mainly three types of EMT 8 (Figure 1).…”

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…12 To date, there are few studies showing promising strategies to treat pulmonary fibrosis. [3][4][5][6][7][8] Bleomycin (BLM) instillation is the most frequently used animal model of lung fibrosis in mice. 9 In this model, it has been shown that J Leukoc Biol.…”

Hydroxycamptothecin Prevents Fibrotic Pathways in Fibroblasts In Vitro

“…First, we observed that HCPT could inhibit abnormally activated fibroblast proliferation and induced fibroblast apoptosis. Studies have shown that the TGF-β1 signaling pathway mediated fibrosis in a variety of tissues (28)(29)(30). Additionally, we reported that TGF-β1 stimulated fibroblast proliferation and tendon tissue adhesion (31,32).…”