Soluble guanylyl cyclase (sGC) is a cGMP-generating enzyme implicated in the control of smooth muscle tone that also regulates platelet aggregation. Moreover, sGC activation has been shown to reduce leukocyte adherence to the endothelium. Herein, we investigated the expression of sGC in a murine model of LPS-induced lung injury and evaluated the effects of sGC inhibition in the context of acute lung injury (ALI). Lung tissue sGC α1 and β1 subunit protein levels were determined by Western blot and immunohistochemistry, and steady-state mRNA levels for the α1 subunit were assessed by real-time PCR. LPS inhalation resulted in a decrease in β1 mRNA levels, as well as a reduction in both sGC subunit protein levels. Decreased α1 and β1 expression was observed in bronchial smooth muscle and epithelial cells. TNF-α was required for the LPS-triggered reduction in sGC protein levels, as no change in α1 and β1 levels was observed in TNF-α knockout mice. To determine the effects of sGC blockade in LPS-induced lung injury, mice were exposed to 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-l-one (ODQ) prior to the LPS challenge. Such pretreatment led to a further increase in total cell number (mainly due to an increase in neutrophils) and protein concentration in the bronchoalveoalar lavage fluid; the effects of ODQ were reversed by a cell-permeable cGMP analog. We conclude that sGC expression is reduced in LPS-induced lung injury, while inhibition of the enzyme with ODQ worsens lung inflammation, suggesting that sGC exerts a protective role in ALI.
|Journal||American Journal of Physiology - Regulatory Integrative and Comparative Physiology|
|Publication status||Published - 1 Apr 2007|