Therapeutic effects of pyrrolidine dithiocarbamate on acute lung injury in rabbits

<p>Abstract</p> <p>Background</p> <p>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is an early characteristic of multiple organ dysfunction, responsible for high mortality and poor prognosis in patients. The present study aims to evaluate therapeutic effects and mechanisms of pyrrolidine dithiocarbamate (PDTC) on ALI.</p> <p>Methods</p> <p>Alveolar-arterial oxygen difference, lung tissue edema and compromise, NF-κB activation in polymorphonuclear neutrophil (PMN), and systemic levels of tumor necrosis factor-alpha (TNFa) and intercellular adhesion molecule-1 (ICAM-1) in rabbits induced by the intravenous administration of lipopolysaccharide (LPS) and treated with PDTC. Production of TNFa and IL-8, activation of Cathepsin G, and PMNs adhesion were also measured.</p> <p>Results</p> <p>The intravenous administration of PDTC had partial therapeutic effects on endotoxemia-induced lung tissue edema and damage, neutrophil influx to the lung, alveolar-capillary barrier dysfunction, and high systemic levels of TNFa and ICAM-1 as well as over-activation of NF-κB. PDTC could directly and partially inhibit LPS-induced TNFa hyper-production and over-activities of Cathepsin G. Such inhibitory effects of PDTC were related to the various stimuli and enhanced through combination with PI3K inhibitor.</p> <p>Conclusion</p> <p>NF-κB signal pathway could be one of targeting molecules and the combination with other signal pathway inhibitors may be an alternative of therapeutic strategies for ALI/ARDS.</p

The Relevance of Leukotriene B4 to the Development of Acute Lung Injury Induced by Lipopolysaccharide

Acute lung injury (ALI) induced by lipopolysaccharide (LPS) develops by the activation of leukocytes via various mediators. Leukotriene B4 (LTB4) has a strong effect on activation and migration of leukocytes. We investigated the role of LTB4 in the chain leading to the development of ALI induced by LPS, by observing how an LTB4 receptor antagonist, ONO-4057, suppresses or mitigates leukocyte activation and migration. The 36 rabbits used in the experiment were divided into 3 groups: C group (control group of 12 rabbits treated with physiological saline solution only); L group (of 12 rabbits treated with 20 ?g/kg LPS) and L-O group (of 12 rabbits treated with, first, 10 mg/kg ONO-4057, then LPS). Blood samples were taken before, 3 h after and 6 h after the injection of drugs; then the rabbits were exsanguinated. The right and left lungs were removed for wet/dry weight ratio and bronchoalveolar lavage fluid (BALF) measurements, respectively. We measured: the leukocyte counts in the peripheral blood, the chemiluminescence (CL) intensity to measure the amount of oxygen free radical species (active oxygen species) production, the LTB4 concentration in the blood, the complement activity levels (CH50), the polymorphonuclear neutrophil elastase (PMN-E) and myeloperoxidase (MPO) levels in BALF, and the wet/dry weight ratio of the right lung. The leukocyte counts in L and L-O rabbits decreased significantly 3 h after LPS injection, then were regained by the 6th h. Regarding CL (with and without zymosan stimulation), there was no significant difference over time for C group. For L group, the zymosan-stimulated CL showed a significant increase at the 6th h, whereas the non-stimulated CL showed significant increases at the 3rd and 6th h. For L-O group, the zymosan-stimulated CL showed a significant increase at the 6th h, whereas the non-stimulated CL increased after 3 h, then slightly decreased after 6 h. The LTB4 levels showed significant increases at the 6th h for both L and L-O groups. The CH50 showed significant decreases at 6th h for both L and L-O groups. The MPO activity in the BALF was significantly high for both the L and L-O groups. There was a tendency for a high PMN-E level in the BALF for L group. The mean wet/dry weight ratio of the right lung was significantly high for L group, compared to both C and L-O groups. Although an inhibitory effect on LTB4 receptors by ONO-4057 failed to prevent leukocyte migration, it successfully suppressed the activity of non-stimulated CL, MPO and PMN-E, and, as a result, prevented the wet/dry weight ratio from increasing