Angiotensin-Converting Enzyme Inhibitors
Although more commonly known for its blood pressure and electrolyte regulatory functions, the renin-angiotensin system (RAS) also plays a vital role in the pathogenesis of ALI. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to generate angiotensin II, which acts on its receptor AT1R to produce alveolar vasoconstriction, increased permeability, edema, and fibrosis. ACE2 is a homologue of ACE that diverts a RAS signal from the AT1R to the angiotensin 2 receptor (AT2R), enabling antagonism of AT1R effects via alveolar vasodilation, decreased permeability, and apoptosis. The significance of ACE2 became apparent during the severe acute respiratory syndrome (SARS) epidemic of 2002, when this enzyme was identified as the receptor for a novel coronavirus, with infection resulting in impaired function, unopposed trafficking of the RAS signal through ACE, and the development of ALI with a mortality of almost 10%.
Much preclinical evidence supports the role the RAS plays in the pathogenesis of ALI, and evidence is now accumulating for the pharmacological targeting of the RAS system to treat ALI. Two variants of the ACE gene (I and D) have been associated with either a protective or a susceptible genotype for both the development of ARDS, and mortality from ARDS, in human studies, with the activity of ACE also being related to the severity of ARDS. A murine study has shown that blocking the RAS, or supplementing recombinant AT2Rs, lessens the severity of ALI. Clinical trials of either ACE inhibition or other modulation of the RAS are awaited.