Effects of COX-2 inhibitor on ventilator-induced lung injury in rats.

BACKGROUND: Mechanical ventilation especially with large tidal volume has been demonstrated to activate inflammatory response inducing lung injury, which could be attenuated by cyclooxygenase (COX)-2 inhibitors. As the main small integral membrane proteins that selectively conduct water molecules' transportation, aquaporin (AQP)-1 downregulation significantly related to lung edema and inflammation. This study aims to investigate the role of AQP1 in ventilator-induced lung injury in rats and evaluates the effects of COX-2 inhibition. METHODS: Forty rats were allocated into four groups, where rats in Groups LD (low volume+DMSO) and LN (low volume+NS-398) were given intravenously 2ml DMSO and 8mg/kg NS-398 (a specific COX-2 inhibitor, dissolved in 2ml DMSO) before 4-hour lower tidal volume ventilation (8ml/kg), respectively, while DMSO and NS-398 were administrated in the same manner before 4-hour injurious ventilation (40ml/kg) in Groups HD (high volume+DMSO) and HN (high volume+NS-398). The arachidonic acid metabolites (6-keto prostaglandin F1α, thromboxane B2), inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, 6, 8) and total protein levels in bronchoalveolar lavage (BAL) fluid and COX-2 mRNA and AQP1 protein expression in lung tissue were detected; water content and lung morphology were also evaluated. RESULTS: Compared to Groups LD and LN, the rats in Groups HD and HN suffered obvious lung morphological changes with higher wet-to-dry weight ratio and lung injury score, and the levels of arachidonic acid metabolites, inflammatory cytokines and total protein in BAL fluid were increased, the expression of COX-2 mRNA was significantly upregulated and AQP1 protein was downregulated in lung tissue (p<0.05). The changes in BAL fluid and the severity of lung injury were attenuated, and AQP1 expression was upregulated in Group HN as compared to HD (p<0.05). CONCLUSIONS: Ventilation with large tidal volume causes inflammatory mediator production and AQP1 downregulation, which could be attenuated by COX-2 inhibition.

Sevoflurane attenuates pulmonary inflammation and ventilator-induced lung injury by upregulation of HO-1 mRNA expression in mice.

BACKGROUND: Mechanical ventilation has been documented to paradoxically cause lung injury. As a commonly used volatile anesthetic, sevoflurane has been proven to possess antiinflammatory and antioxidative properties. This study aims to investigate the protective effects of sevoflurane on inflammation and ventilator-induced lung injury during mechanical ventilation in healthy mice. METHODS: The adult healthy mice were divided into four groups, each consisting of ten subjects: mice in group Con-L(VT) and group Sev-L(VT) were ventilated with tidal volumes of 8 mL/kg for 4 hours, while those in group Con-H(VT) and group Sev-H(VT) were ventilated with tidal volumes of 16 mL/kg instead. Control mice (group Con-L(VT) and Con-H(VT)) were subjected to fresh air, while sevoflurane-treated mice (groups Sev- L(VT) and Sev-H(VT)) were subjected to air mixed with 1 vol% sevoflurane. After 4 hours of ventilation, the bronchoalveolar lavage (BAL) fluid was collected and analyzed for the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10. Lung homogenates were harvested to detect the expression of nuclear factor-kappa B (NF-κB) and heme oxygenase (HO)-1 mRNA by reverse transcription-polymerase chain reaction method. Lung damage was evaluated using the modified Ventilator-Induced Lung Injury histological scoring system. RESULTS: Compared to group Con-L(VT), the levels of TNF-α, IL-1ß, IL-6, and IL-10 in BAL fluid, mRNA expressions of NF-κB and HO-1 in lung tissue, and lung injury scores were significantly increased in group Con-H(VT); compared to group Con-H(VT), group Sev-H(VT) BAL samples showed decreased levels of TNF-α, IL-1ß, and IL-6; they also showed increased levels of IL-10, the downregulation of NF-κB mRNA, and HO-1 mRNA upregulation; the lung injury scores were significantly lower in group Sev-H(VT) than group Con-H(VT). CONCLUSION: Mechanical ventilation with high tidal volume might lead to lung injury, which could be significantly, but not completely, attenuated by sevoflurane inhalation by inhibiting the NF-κB-mediated proinflammatory cytokine generation and upregulating HO-1 expression.

Diabetes increases inflammation and lung injury associated with protective ventilation strategy in mice.

BACKGROUND: Mechanical ventilation may paradoxically cause lung injury. Protective mechanical ventilation strategy utilizing low tidal volume and high frequency has been shown to attenuate inflammation and reduce mortality in non-diabetic patients. The purpose of this present study was to observe the effects of diabetes on inflammation and lung injury in mice with protective ventilation strategy. METHODS: Forty mice were included in our study. The mice in Group Dia-MV and Con-MV were subjected to 4 hour-ventilation. And the mice in Group Dia-SB and Con-SB were exposed to room air breathing spontaneously for 4h. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), superoxide dismutase (SOD) and malondialdehyde (MDA) levels in serum were detected and the expression of inflammatory cytokine mRNA was also determined in lung tissue. Lung damage was assessed using a modified lung injury score. RESULTS: The serum levels of TNF-α, IL-6, and IL-10 in Group Dia-MV were significantly higher than those in Group Dia-SB or Group Con-MV or Group Con-SB (P<0.05). Quantitative RT-PCR analysis of pro-inflammatory cytokines in lung homogenates presented similar results. The mice in Group Dia-MV suffered obvious lung histological changes, whose lung injury scores were significantly higher in Group Dia-SB as compared to Group Con-SB , Group Con-MV or Group Dia-SB (P<0.05). CONCLUSIONS: Diabetes increased the inflammation reaction and associated lung injury in mice in spite of the protective mechanical ventilation strategy based on low tidal volumes and high frequency.

Ischemic preconditioning attenuates pulmonary dysfunction after unilateral thigh tourniquet-induced ischemia-reperfusion.

BACKGROUND: Acute lung injury is a recognized complication of lower limb ischemia-reperfusion that has been demonstrated experimentally and in the clinical setting of aortic surgery. The application of a tourniquet can cause lower limb ischemia-reperfusion in orthopedic surgery. We studied the effect of unilateral thigh tourniquet-induced lower limb ischemia-reperfusion on pulmonary function, and the role of ischemic preconditioning in attenuating pulmonary dysfunction. METHODS: Thirty ASA I or II patients scheduled for lower extremity surgery were randomized into 2 groups: a limb ischemia-reperfusion group with tourniquet application (ischemia-reperfusion group, n = 15) and an ischemia preconditioning group (preconditioning group, n = 15), in which patients received 3 cycles of 5 minutes of ischemia, alternating with 5 minutes of reperfusion before extended use of the tourniquet. Blood gas, plasma malondialdehyde, and serum interleukin-6 (IL-6), IL-8, and IL-10 levels were measured just before tourniquet inflation, 1 hour after inflation and 2 hours, 6 hours, and 24 hours after tourniquet deflation. Arterial-alveolar oxygen tension ratio, alveolar-arterial oxygen tension difference, and respiratory index also were calculated. RESULTS: In comparison with the baseline values, arterial Po(2) and arterial-alveolar oxygen tension ratio were decreased, while alveolar-arterial oxygen tension difference and respiratory index were increased significantly 6 hours after tourniquet deflation in both groups (P < 0.01). However, these changes were less significant in the ischemic preconditioning group than those in the lower limb ischemia-reperfusion group (P < 0.01). Similarly, the increases in the malondialdehyde, IL-6, and IL-8 from 2 hours to 24 hours after release of the tourniquet in the lower limb ischemia-reperfusion group were attenuated by ischemic preconditioning. CONCLUSIONS: Pulmonary gas exchange is impaired after lower limb ischemia-reperfusion associated with the clinical use of a tourniquet for lower limb surgery. Ischemic preconditioning preceding tourniquet-induced ischemia attenuates lipid peroxidation and systemic inflammatory response and mitigates pulmonary dysfunction.