title: OPC-6535, a superoxide anion production inhibitor, attenuates acute lung injury.
abstract: A large body of evidence has demonstrated that inhibition of the neutrophil's oxidant burst attenuates sepsis-induced acute lung injury. The present study sought to evaluate the ability of OPC-6535, a superoxide anion production inhibitor, to attenuate sepsis-induced acute lung injury. Four groups of swine were anesthetized, ventilated, and studied for 5 hr. Following surgical preparation, control (n = 10) and OPC-control (n = 2) animals received a 1-hr infusion of sterile saline. Sepsis was induced with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. Untreated septic animals (n = 10) received no treatment. Animals treated with OPC-6535 (n = 6) received a 1 mg/kg bolus of OPC-6535 15 min prior to initiation of the bacterial infusion. Changes in systemic and pulmonary hemodynamics, arterial oxygen tension, bronchoalveolar lavage protein and neutrophil content, neutrophil integrin expression, neutrophil oxidant burst, and lung myeloperoxidase content were used as outcome measures. Treatment with OPC-6535 significantly reduced acute lung injury, as indicated by improved bronchoalveolar lavage protein and neutrophil content, resulting in a significant improvement in arterial oxygenation. Treatment with OPC-6535 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutrophils from animals with both treated and untreated sepsis exhibited significant up-regulation of CD18 and production of increased levels of oxidants, indicating significant activation when compared to neutrophils from control animals. Although animals treated with OPC-6535 produced 25% less superoxide anion than untreated septic animals, this decrease was not statistically significant. Treatment of animals with OPC-6535 prior to the onset of sepsis produced significant protection against acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis.
authors.affiliation: Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Bloomfield
authors.forename: P C
authors.initials: PC
authors.lastname: Ridings
authors.forename: C R
authors.initials: CR
authors.lastname: Blocher
authors.forename: B J
authors.initials: BJ
authors.lastname: Fisher
authors.forename: H J
authors.initials: HJ
authors.lastname: Sugerman
authors.forename: H
authors.initials: H
authors.lastname: Nagamoto
authors.forename: A A
authors.initials: AA
authors.lastname: Fowler
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000838:Anions / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D002453:Cell Cycle; D004195:Disease Models, Animal; D004727:Endothelium / Q000201:enzymology / Q000276:immunology; D006439:Hemodynamics; D016023:Integrins / Q000032:analysis; D007958:Leukocyte Count; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000032:analysis; D011652:Pulmonary Circulation; D016897:Respiratory Burst / Q000276:immunology; D018805:Sepsis / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000838:Anions; D016023:Integrins; D013844:Thiazoles; D013481:Superoxides; D009195:Peroxidase; C108965:tetomilast; D010100:Oxygen