Functional Microcirculation Is Lost in Early Airway Fibrosis

Ventilator-induced lung injury (VILI) is characterized by inflammation and apoptosis. The mechanism by which mechanical ventilation triggers these processes is poorly understood. Recently, a role for angiotensin-converting enzyme (ACE) via angiotensin II (Ang II) and/or bradykinin in acute lung injury was proposed. We assessed whether ACE and, if so, Ang II and/ or bradykinin, are implicated in inflammation and apoptosis by mechanical ventilation. Rats were ventilated for 4 hours with low, intermediate, or high pressure amplitudes in the absence or presence of the ACE inhibitor captopril. Nonventilated animals served as controls. ACE activity, Ang II, and bradykinin, as well as inflammatory parameters (levels of total protein, macrophage inflammatory protein-2, and interleukin-6) and that of cell necrosis (lactate dehydrogenase [LDH] activity), were determined. Activated caspase-3–positive cells were assessed as a measure of apoptosis in lung tissue. Bronchoalveolar lavage fluid (BALF) ACE activity, levels of total protein, inflammatory parameters, and the number of apoptotic cells were increased, particularly in the intermediate pressure amplitude group as compared with the control group. Blocking ACE activity by captopril attenuated the inflammatory response and apoptosis in this latter group. Similar results were obtained by blocking Ang II receptors, but blocking bradykinin receptors did not attenuated the anti-inflammatory and antiapoptotic effects of captopril. Ventilation with high pressure amplitudes resulted in severe lung tissue damage (necrosis) as indicated by markedly increased LDH activity and loss of epithelial barrier function. Captopril did not attenuate BALF ACE activity or necrosis in this group. We conclude that inflammation and apoptosis in VILI is, at least in part, due to ACE-mediated Ang II production.