Binding to ACE2 leading to lung fibrosis

Young Jun Kim¹, Ian Choi¹, Jihun Yang², Chung Seok^2,3 Brigitte Landesmann⁴, Laure-Alix Clerbaux⁴  and Penny Nymark⁵

¹Korea Institute of Science and Technology (KIST) Europe, Saarbrücken 66123, Germany, ² NEXT&BIO, South Korea,  ³KU-KIST Graduate School of Converging Science and Technology, South Korea ⁴ F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM, Directorate F – Health, Consumers and Reference Materials Joint Research Centre, European Commission  ⁵ Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden 

Lung fibrosis has a distinct point in idiopathic pulmonary fibrosis from the renin-angiotensin pathway. this system is reported in many works of literature to share many immune/inflammatory responses to lung damage. When ACE2 activity is inhibited, Ang II is not effectively converted into Ang-(1-7). Because of this, the levels of proinflammatory Ang II are increased and accumulated, while the levels of anti-inflammatory Ang-(1-7) are reduced. Most importantly, the Inhibition of ACE2 was shown to enhance the level of Ang II peptides which is a ligand for type 1 angiotensin receptor (AT1R) and is considered one of the risk factors for lung fibrosis, vasoconstriction, endothelial dysfunction, and cell death. The imbalance of the renin-angiotensin system (RAS) plays a critical role in the fibrogenesis and inflammation damage of many organs. Especially the inhibition of membrane ACE-2 enzymatic activity has shown promising potential in the Molecular initiation event which leads to pulmonary fibrosis. This AOP describes the role of ACE-2 in fibrotic damage of the lung as an adverse outcome through the fibrogenic components, proinflammatory cytokines, and oxygen deficiency.

ACE2 is an essential enzyme of blood pressure regulation in the renin-angiotensin system. ACE2 is primarily expressed on type II alveolar epithelial cells within the respiratory system. Angiotensin-converting enzyme (ACE) synthesizes the dominant vasoconstriction, inflammatory and profibrotic angiotensin II (Ang II) through its carboxypeptidase function on the decapeptide angiotensin I. In the meantime, Angiotensin-converting enzyme 2 (ACE2) is an exopeptidase that catalyzes the conversion of angiotensin Il to the conversion of angiotensin 1-7 function as vasodilation, anti-inflammation, and anti-fibrotic.  This AOP describes the dysfunction of membrane ACE2, which results in a high level of angiotensin Ang II synthesized by ACE, which can further lead to pulmonary fibrosis by excessive collagen deposition as the most potent profibrotic factor.