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INFLAMMATION AND CYTOKINES

Soluble guanylyl cyclase expression is reduced in LPS-induced lung injury

¹George P. Livanos and Marianthi Simou Laboratories, Evangelismos Hospital, 1st Department of Pulmonary and Critical Care, University of Athens, Athens, Greece; ²2nd Department of Critical Care, Attikon University Hospital, University of Athens Medical School, Haidari (Athens); and ³Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece

Submitted 22 May 2006 ; accepted in final form 28 December 2006

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 1 and 1 subunit protein levels were determined by Western blot and immunohistochemistry, and steady-state mRNA levels for the 1 subunit were assessed by real-time PCR. LPS inhalation resulted in a decrease in 1 mRNA levels, as well as a reduction in both sGC subunit protein levels. Decreased 1 and 1 expression was observed in bronchial smooth muscle and epithelial cells. TNF- was required for the LPS-triggered reduction in sGC protein levels, as no change in 1 and 1 levels was observed in TNF- 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.

endotoxin; guanosine 3',5'-cyclic monophosphate; acute lung injury

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