MKP‐1 Deficiency Augments LPS‐Induced NO Production in the Lung

Abstract

Pulmonary vasoreactivity is altered in neonatal pulmonary inflammatory diseases such as bronchopulmonary dysplasia, which can lead to ventilation‐perfusion (V/Q) mismatch. Mitogen‐activated protein kinase phosphatase (MKP‐1) is essential in limiting the pro‐inflammatory response to lipopolysaccharide (LPS). We hypothesized that LPS treatment in Mkp‐1−/− mice would result in altered pulmonary vasomotor tone due to augmented expression of inducible nitric oxide synthase (iNOS). We tested this hypothesis by treating Mkp‐1−/− mice and their wildtype littermates with 5 mg/kg LPS ip at 1 and 12 h prior to lung isolation and perfusion. Exhaled NO (exNO) was collected at the 12 h time point and measured. We found that baseline PVR was not different in lungs isolated from untreated Mkp‐1−/− mice or their wildtype littermates. However, baseline PVR was lower at 1 h in lungs from LPS treated Mkp‐1−/− mice compared to their wildtype littermates. ExNO was greater in isolated lungs from Mkp‐1−/− mice compared to their wildtype littermates. These results demonstrate that deficiency of MKP‐1 results in lower PVR, which is mediated by augmented pulmonary NO production. We speculate that targeting iNOS gene expression early in pro‐inflammatory states will prevent altered pulmonary vasomotor reactivity and improve V/Q matching.