Published ahead of print on May 13, 2005, doi:10.1164/rccm.200501-034OC Am. J. Respir. Crit. Care Med., Volume 172, Number 3, August 2005, 334-343 A more recent version of this article appeared on August 1, 2005
Submitted on January 10, 2005 5-Lipoxygenase Deficiency Prevents Respiratory Failure During Ventilator-induced Lung InjuryPietro Caironi1,1 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 3 Cardiovascular Research Center of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: wzapol{at}partners.org.
Rationale: Mechanical ventilation with high tidal volumes (HVT) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions preserving systemic oxygenation during pulmonary injury. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. Objectives: To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HVT and to evaluate the role of LTs in ventilator-induced lung injury (VILI). Methods: We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low tidal volumes (LVT) or HVT. Results: In wild-type mice, HVT, but not LVT, increased pulmonary vascular permeability and edema formation, impaired systemic oxygenation, and reduced survival. HPV, as reflected by the increase in left pulmonary vascular resistance (LPVR) induced by left mainstem bronchus occlusion (LMBO), was markedly impaired in animals ventilated with HVT. HVT ventilation increased bronchoalveolar lavage levels of LTs and neutrophils. In 5LO-deficient mice, the HVT-induced increase of pulmonary vascular permeability and worsening of respiratory mechanics were markedly attenuated, systemic oxygenation was preserved, and survival increased. Moreover, in 5LO-deficient mice, HVT ventilation did not impair the ability of LMBO to increase LPVR. Administration of MK886, a 5LO-activity inhibitor, or MK571, a selective cysteinyl-LT1 receptor antagonist, largely prevented VILI. Conclusions: These results indicate that LTs play a central role in the lung injury and impaired oxygenation induced by HVT ventilation. Key words: ventilator-induced lung injury, hypoxic pulmonary vasoconstriction, leukotrienes
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