Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J 2 (15d-PGJ 2 ) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ 2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ 2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor g or generation of reactive oxidative species. CDDO and 15d-PGJ 2 inhibited the extracellular signal-regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease.

Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways

“…However, studies on other airway diseases, such as cystic fibrosis, idiopathic pulmonary fibrosis, and lung cancer, support a central role for Tgm2 in aberrant pulmonary wound healing and have led to the development of Tgm2 inhibitors for the treatment of these diseases. 54,[56][57][58][59] Thus airway Tgm2 levels should be assessed in asthmatic patients and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and correlated to disease severity to investigate whether Tgm2 might represent a therapeutic target in asthma or nasal polyposis. Because Tgm2 expression can be modulated by DNA methylation 60 or oxidative stress, 61 which are both strongly influenced by age, 62,63 future studies should clarify the role of these factors in age differences in levels of Tgm2 and its regulatory targets in the setting of airway inflammation.…”

Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

“…Therefore, less conventional methods that abolish TG2 activity by limiting its expression are also being pursued. Upstream inhibitors of the extracellular signal-regulated kinase (ERK) pathway that down-regulate TG2 expression and small interfering RNA (siRNA) have successfully demonstrated preclinical potential as antifibrotic therapies (63,64). TG2 siRNA coupled with liposome delivery yielded effective organ-specific targeting to the liver and lungs in mice (64).…”

Fibulin-5 as a potential therapeutic target in COPD

“…[18] Regarding the therapeutic potential of TG2, a recent study demonstrated that two small electrophilic compounds inhibit TG2 and its pro-fibrotic activities in human lung fibroblasts. [20] The in vivo therapeutic potential of these compounds in fibrotic lung disease is of great interest, also in relation to fibulin-5 expression.…”