Angiotensin-converting enzyme 2 in lung diseases

Abstract

The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease. Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS). ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections. In the lung, ACE2 protects against acute lung injury in several animal models of ARDS. Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury. Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.

Figure 1

Current view of the RAS in pulmonary hypertension and pulmonary fibrosis. ANG I serves as a substrate for both ACE and ACE2. ANG II is known to act as vasoconstrictor as well as a mitogen for smooth muscle cells or fibroblasts, mainly through the AT₁ receptor. The function of angiotensin-(1–9) is not well understood. Both ACE and ACE2 are involved in the production of the vasodilator peptide angiotensin-(1–7).

Figure 2

Schematic diagram of the proposed role of the RAS in development of severe ARDS. In acute lung injury such as SARS-CoV infections, acid aspiration, pneumonias or sepsis, the generation of ANG II from ANG I is enhanced by ACE. ANG II contributes to acute lung failure through stimulation of the AT₁ receptor, whereas ACE2 and the AT₂ receptor negatively regulate this pathway and protect from acute lung failure. However, additional ACE2-regulated, but ANG II-independent, pathways seem to also contribute to ARDS.