Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of lung inflammation through proinflammatory eicosanoids. A previous in vitro experiment showed a possible role of cell surface receptor for sPLA2 (PLA2R) in the clearance of extracellular sPLA2. PLA2R and groups IB and X sPLA2 are expressed in the lung. This study examined a pathogenic role of PLA2R in airway inflammation using PLA2R-deficient (PLA2R−/−) mice. Airway inflammation was induced by immunosensitization with OVA. Compared with wild-type (PLA2R+/+) mice, PLA2R−/− mice had a significantly greater infiltration of inflammatory cells around the airways, higher levels of groups IB and X sPLA2, eicosanoids, and Th2 cytokines, and higher numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid after OVA treatment. In PLA2R−/− mice, intratracheally instilled [125I]-labeled sPLA2-IB was cleared much more slowly from bronchoalveolar lavage fluid compared with PLA2R+/+ mice. The degradation of the instilled [125I]-labeled sPLA2-IB, as assessed by trichloroacetic acid-soluble radioactivity in bronchoalveolar lavage fluid after instillation, was lower in PLA2R−/− mice than in PLA2R+/+ mice. In conclusion, PLA2R deficiency increased sPLA2-IB and -X levels in the lung through their impaired clearance from the lung, leading to exaggeration of lung inflammation induced by OVA treatment in a murine model.

Rationale: Recent evidence indicates that the biological effects of secretory phospholipase A 2 (sPLA 2 ) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA 2 (PLA 2 receptor 1 [PLA 2 R]) and its high-affinity ligands (including sPLA 2 -IB, sPLA 2 -IIE, and sPLA 2 -X) are expressed in the infarcted myocardium. Objective: This study asked whether PLA 2 R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA 2 R (PLA 2 R –/– ). Methods and Results: MI was induced by permanent ligation of the left coronary artery. PLA 2 R –/– mice exhibited higher rates of cardiac rupture after MI compared with PLA 2 R wild-type (PLA 2 R +/+ ) mice (46% versus 21%, respectively; P =0.015). PLA 2 R –/– mice had a 31% decrease in collagen content and a 45% decrease in the number of α-smooth muscle actin–positive fibroblasts in the infarcted region compared with PLA 2 R +/+ mice. PLA 2 R was primarily found in myofibroblasts in the infarcted region. PLA 2 R –/– myofibroblasts were impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA 2 -IB. Binding of sPLA 2 -IB to PLA 2 R promoted migration and proliferation of myofibroblasts through functional interaction with integrin β1, independent of the catalytic activity of sPLA 2 -IB. In rescue experiments, the injection of PLA 2 R +/+ myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA 2 R –/– mice. Conclusions: PLA 2 R deficiency increased the susceptibility to post-MI cardiac rupture through impaired healing of the infarcted region. This might be partly explained by a reduction in integrin β1–mediated migratory and proliferative responses of PLA 2 R –/– myofibroblasts.

Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

sPLA(2)-V plays an important role in the pathogenesis of myocardial I/R injury partly in concert with the activation of cPLA(2).

Kugiyama K. Group X secretory phospholipase A2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice.