Transglutaminase 2 knockout mice are protected from bleomycin‐induced lung fibrosis with preserved lung function and reduced metabolic derangements

• Published in: Physiological reports Vol. 12; no. 12; pp. e16012 - n/a
• Main Authors: Freeberg, Margaret A. T., Thatcher, Thomas H., Camus, Sarah V., Huang, Linghong, Atkinson, John, Narrow, Wade, Haak, Jeannie, Dylag, Andrew M., Cowart, L. Ashley, Johnson, Timothy S., Sime, Patricia J.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc; Wiley
• Subjects: Aerobic capacity; Animals; Bleomycin; Collagen; Extracellular matrix; Fibroblasts; Fibrosis; Glycolysis; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Ketamine; L-Lactate dehydrogenase; Lactic acid; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Male; Metabolism; metabolomics; Mice; Mice, Inbred C57BL; Mice, Knockout; Original; Protein Glutamine gamma Glutamyltransferase 2 - metabolism; Proteins; pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Respiratory function; transglutaminase; Transglutaminase 2; Transglutaminases - genetics; Transglutaminases - metabolism; United States > US; Germany; transglutaminase; metabolism; metabolomics; pulmonary fibrosis
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.16012

Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase 2 (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFβ. This study assessed physiologic pulmonary function and metabolic alterations in the mouse bleomycin model with TG2 genetic deletion. TG2‐deficient mice demonstrated attenuated the fibrosis and preservation of lung function, with significant reduction in elastance and increases in compliance and inspiratory capacity compared to control mice treated with bleomycin. Bleomycin induced metabolic changes in the mouse lung that were consistent with increased aerobic glycolysis, including increased expression of lactate dehydrogenase A and increased production of lactate, as well as increased glutamine, glutamate, and aspartate. TG2‐deficient mice treated with bleomycin exhibited similar metabolic changes but with reduced magnitude. Our results demonstrate that TG2 is required for a typical fibrosis response to injury. In the absence of TG2, the fibrotic response is biochemically similar to wild‐type, but lesions are smaller and lung function is preserved. We also show for the first time that profibrotic pathways of tissue stiffening and metabolic reprogramming are interconnected, and that metabolic disruptions in fibrosis go beyond glycolysis. Tissue transglutaminase 2 (TG2) knockout mice demonstrated preserved lung function and reduced lesion area following bleomycin injury. Bleomycin fibrotic injury is associated with energy and amino acid metabolic changes. These metabolic changes are similar but overall reduced in magnitude in the TG2 KO mice. We also show for the first time that profibrotic pathways of tissue stiffening and metabolic reprogramming are interconnected, and that metabolic disruptions in fibrosis go beyond glycolysis.