5-Lipoxygenase Deficiency Prevents Respiratory Failure during Ventilator-induced Lung Injury

Abstract

Rationale: Mechanical ventilation with high VT (HVT) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to wellventilated 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. Methods: We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low VT (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 induced by left mainstem bronchus occlusion, 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 left mainstem bronchus occlusion to increase left pulmonary vascular resistance. Administration of MK886, a 5LO-activity inhibitor, or MK571, a selective cysteinyl-LT 1 receptor antagonist, largely prevented ventilator-induced lung injury. Conclusions: These results indicate that LTs play a central role in the lung injury and impaired oxygenation induced by HVT ventilation. Keywords: hypoxic pulmonary vasoconstriction; leukotrienes; ventilatorinduced lung injuryExcessive stretching of lung parenchyma, by ventilation with large Vt, progressively injures the structure and gas-exchanging efficiency of the lung (1-3). Common alterations of the respiratory system during ventilator-induced lung injury (VILI) include pulmonary edema, because of increased permeability of the alveolar-capillary membrane, and hypoxemia, as a consequence of intrapulmonary right-to-left shunting (especially in the terminal stages of VILI). During the development of acute lung injury, systemic oxygenation is maintained by hypoxic pulmonary vasoconstriction (HPV), a physiologic property of the pulmonary microvasculature that diverts blood flow from hypoxic/poorly ventilated lung regions toward more normally ventilated lung regions. Experimental and clinical studies have reported that HPV is impaired in lung injury induced by endotoxemia (4, 5) and in patients affected by acute respiratory distress syndrome (ARDS) (6). However, whether or not impairment of HPV contributes to the hypoxemia associated with VILI has not been reported.The mechanisms contributing to the development of VILI have been extensively investigated (7). Excessive lung inflation c...

Time to generate ventilator-induced lung injury among mammals with healthy lungs: a unifying hypothesis

“…Thirdly, based upon the pathological alteration of the lung during the development of VILI, it is likely that the initial lung strain applied does not remain constant throughout the period in which mechanical ventilation is applied, but it rather progressively increases. In fact, as the interstitial oedema begins to develop as a consequence of the altered permeability of the alveolar capillary membrane, FRC will progressively shrink, leading to a further increase in the lung strain actually applied and therefore to the ''avalanche'' process often characterizing the manifestation of VILI [9,20,21].…”

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

“…The resulting leukotrienes are elevated in ALI (45). In gene-targeted deficient mice or in animals treated with ALOX5 inhibitors, neutrophil infiltration and lavage protein are decreased after various forms of lung injury (89)(90)(91)(92)(93)(94). Moreover, survival is increased after ventilator-induced lung injury (91).…”

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

“…Forward modeling using actual airway tree structure data derived from airway casts of bronchial trees has further refined the application of the constant-phase models for more accurate analysis of tissue and airway mechanical properties during ALI (41). Non-invasive imaging methods available to evaluate lung injury for research include x-ray films, high-resolution computed tomography (HRCT), magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescence tomography (65,206,337,428,461). These imaging techniques are attractive because multiple sequential measurements can be made over time without sacrificing the animal, and any technological improvements can be readily translated to patient care (430).…”