Dickkopf1 Promotes Pulmonary Fibrosis upon Bleomycin-Induced Lung Injury

• Published in: The American journal of pathology Vol. 193; no. 9; pp. 1130 - 1142
• Main Authors: Sung, Eun-Ah, Park, Min Hee, Henegariu, Octavian, Sime, Patricia J, Chae, Wook-Jin
• Format: Journal Article
• Language: English
• Published: United States American Society for Investigative Pathology 01.09.2023
• Subjects: Animals; Bleomycin - toxicity; Collagen - metabolism; Humans; Inflammation - pathology; Lung - pathology; Lung Injury - pathology; Mice; Pneumonia - metabolism; Pulmonary Fibrosis - pathology; Regular; Transforming Growth Factor beta1 - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2023.05.009

Orchestration of inflammation and tissue repair processes is critical to maintaining homeostasis upon tissue injury. Tissue fibrosis is a pathological process characterized by aberrant accumulation of extracellular matrix proteins, such as collagen, upon injury. Dickkopf1 (DKK1) is a quintessential Wnt antagonist. The role of DKK1 in bleomycin (BLM)-induced lung injury and fibrosis model remains elusive. This study shows that BLM-induced lung injury markedly elevated DKK1 protein expressions in the lungs in mice, consistent with human pulmonary fibrosis patient lung tissues. The elevated DKK1 levels coincided with immune cell infiltration and collagen deposition. Notably, the reduced expression of DKK1 in Dkk1 hypomorphic doubleridge (Dkk1 ) mice abrogated BLM-induced lung inflammation and fibrosis. Immune cell infiltration, collagen deposition, expression of profibrotic cytokine transforming growth factor β1 (TGF-β1), and extracellular matrix protein-producing myofibroblast marker α-smooth muscle actin (α-SMA) were reduced in Dkk1 mice. Consistent with these results, local DKK1 antibody administration after BLM-induced lung injury substantially decreased lung inflammation and fibrosis phenotypes. Taken together, these results demonstrate that DKK1 is a proinflammatory and profibrotic ligand that promotes inflammation and fibrosis upon BLM-induced lung injury, placing it as an attractive molecular target for dysregulated pulmonary inflammation and tissue repair.