A potent inhibitor of cytosolic phospholipase A₂, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice

Abstract

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

Identification of Annexin 1 as a Novel Autoantigen in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

“…Annexin 1 inhibits phospholipase A 2 , the first enzyme in the metabolism of eicosanoids, and it has been proposed that this inhibition and the resulting decrease in arachidonic acid release are the basis of the antiinflammatory effect (38). It has been reported that cytosolic phospholipase A 2 plays a pivotal role in the pathogenesis of pulmonary fibrosis, and that disruption of the gene encoding cytosolic phospholipase A 2 significantly attenuates pulmonary fibrosis (39). 2) The second effect relates to a reduction in the recruitment of blood-borne cells into the surrounding tissues (40).…”

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells

“…inhibited phorbol ester-induced chronic ear oedema (Malaviya et al, 2006). Oral application of AACOCF3 also prevented the development of airway hyperresponsiveness in a mouse asthma model (Malaviya et al, 2006) and reduced acute lung injury induced by septic syndrome in mice (Nagase et al, 2003). AACOCF3 also has beneficial effects in a mouse model of experimental autoimmune encephalomyelitis, which is an inflammatory demyelinating disease of the CNS that results in CNS lesions (Kalyvas and David, 2004).…”

Eicosanoids as Risk and Prognostic Factors for Acute Respiratory Distress Syndrome in Sepsis Patients

“…These antagonists reduced pulmonary extravascular water contents and bronchoalveolar lavage fluid protein concentrations. Moreover, cytosolic phospholipase A 2 (cPLA 2 ) is important in the pathogenesis of sepsis-induced ARDS, and LTB 4 is probably the major mediator of polymorphonuclear neutrophil infiltration among the cPLA 2 products [24,25]. The results of the present study indicate that LTB 4 is a factor for ARDS treatments in sepsis patients rather than a prognostic factor.…”