title: Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation.
abstract: Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.
authors.affiliation: 1 George P. Livanos and Marianthi Simou Laboratories, Evangelismos Hospital, First Department of Pulmonary and Critical Care, and.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Glynos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Toumpanakis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Loverdos
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Karavana
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Christina
authors.initials: C
authors.lastname: Magkou
authors.forename: Maria
authors.initials: M
authors.lastname: Dettoraki
authors.forename: Fotis
authors.initials: F
authors.lastname: Perlikos
authors.forename: Athanasia
authors.initials: A
authors.lastname: Pavlidou
authors.forename: Vasilis
authors.initials: V
authors.lastname: Kotsikoris
authors.forename: Stavros
authors.initials: S
authors.lastname: Topouzis
authors.forename: Stamatios E
authors.initials: SE
authors.lastname: Theocharis
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
mesh_terms: D000403:Airway Resistance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D006152:Cyclic GMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008173:Lung Diseases, Obstructive / Q000188:drug therapy / Q000201:enzymology*; D055370:Lung Injury / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL
chemical_list: D001565:Benzoates; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: lung injury; soluble guanylyl cyclase; tracheal banding