Subject(s)
Enzyme Inhibitors/chemical synthesis , Phospholipases A/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Cell Line , Cytosol/enzymology , Dinoprostone/biosynthesis , Eicosanoids/biosynthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Leukotriene C4/biosynthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
Group IIA secretory phospholipase A(2) (sPLA(2)) has been implicated in a variety of inflammatory diseases including acute lung injury (ALI); however, the role of sPLA(2) in this disorder remains unclear. The aim of the present investigation was to examine the role of this enzyme in a model of ALI induced by oleic acid (OA) in rabbits by testing human group IIA phospholipase A(2) (PLA(2)) inhibitor, S-5920/LY315920Na. Experimental groups consisted of a saline control group (n = 8), an OA control group (n = 10) infused intravenously with OA (0.1 ml/kg/h for 2 h), and three groups given OA + S-5920/LY315920Na (three different doses, n = 8, respectively). Infusion of OA provoked pulmonary hemorrhage and edema formation, protein leakage, and massive neutrophil infiltration, resulting in severe hypoxemia and impaired lung compliance. PLA(2) activity was detected in the bronchoalveolar lavage fluid (BALF), but not plasma, which correlated well with severity of lung injury in this model. Pretreatment with S-5920/LY315920Na diminished the OA-induced PLA(2) activity in the BALF and dose-dependently attenuated the previously described lung injury induced by OA, accompanied by protection against lung surfactant degradation and production of thromboxane A(2) (TXA(2)) and leukotriene B(4) (LTB(4)). S-5920/LY315920Na also inhibited the OA-induced production of interleukin-8 (IL-8), both in plasma and BALF. Thus, sPLA(2) appears to play a key role in OA-induced lung injury, suggesting that the group IIA PLA(2) inhibitor may be a promising agent for patients with acute respiratory distress syndrome (ARDS).
Subject(s)
Phospholipases A/physiology , Respiratory Distress Syndrome/physiopathology , Acetates/pharmacokinetics , Acetates/pharmacology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Capillary Permeability , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Extravascular Lung Water/physiology , Group II Phospholipases A2 , Indoles/pharmacokinetics , Indoles/pharmacology , Interleukin-8/metabolism , Keto Acids , Leukotriene B4/metabolism , Lung/blood supply , Lung/pathology , Lung Compliance , Male , Oleic Acid , Oxygen/blood , Phospholipases A/antagonists & inhibitors , Phospholipases A/metabolism , Phospholipids/analysis , Pulmonary Edema/physiopathology , Rabbits , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology , Thromboxane A2/metabolismABSTRACT
Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.
