Phospholipase A2 in Experimental Allergic Bronchitis: A Lesson from Mouse and Rat Models

Abstract

BackgroundPhospholipases A2 (PLA2) hydrolyzes phospholipids, initiating the production of inflammatory lipid mediators. We have previously shown that in rats, sPLA2 and cPLA2 play opposing roles in the pathophysiology of ovalbumin (OVA)-induced experimental allergic bronchitis (OVA-EAB), an asthma model: Upon disease induction sPLA2 expression and production of the broncho-constricting CysLTs are elevated, whereas cPLA2 expression and the broncho-dilating PGE2 production are suppressed. These were reversed upon disease amelioration by treatment with an sPLA2 inhibitor. However, studies in mice reported the involvement of both sPLA2 and cPLA2 in EAB induction.ObjectivesTo examine the relevance of mouse and rat models to understanding asthma pathophysiology.MethodsOVA-EAB was induced in mice using the same methodology applied in rats. Disease and biochemical markers in mice were compared with those in rats.ResultsAs in rats, EAB in mice was associated with increased mRNA of sPLA2, specifically sPLA2gX, in the lungs, and production of the broncho-constricting eicosanoids CysLTs, PGD2 and TBX2 in bronchoalveolar lavage (BAL). In contrast, EAB in mice was associated also with elevated cPLA2 mRNA and PGE2 production. Yet, treatment with an sPLA2 inhibitor ameliorated the EAB concomitantly with reverting the expression of both cPLA2 and sPLA2, and eicosanoid production.ConclusionsIn both mice and rats sPLA2 is pivotal in OVA-induced EAB. Yet, amelioration of asthma markers in mouse models, and human tissues, was observed also upon cPLA2 inhibition. It is plausible that airway conditions, involving multiple cell types and organs, require the combined action of more than one, essential, PLA2s.

Phospholipase A2-dependent Release of Inflammatory Cytokines by Superantigen-Stimulated Nasal Polyps of Patients with Chronic Rhinosinusitis

“…Similarly to the suppression of inflammatory cytokine production by SAE-stimulated NPDCs observed here under treatment with Dexa in both the rat and mouse EAB models studied previously, 11,35,40 regulation of PLA 2 expression ameliorated the disease clinical manifestations, concomitantly with bringing the biochemical markers (PLA 2 expression, eicosanoid, and cytokine production) to their basal, normal levels. The findings of the present study, which showed the involvement of sPLA 2 isoforms in CRwNP induction, whereas cPLA 2 is associated with its resolution, further support the pivotal role of sPLA 2 activities in the pathophysiology of airway conditions, and present the inhibition of sPLA 2 as a therapeutic target for the treatment of CRS and inflammatory airway pathologies in general.…”

“…RNA was purified from the NPDC by using Trizol reagent, as previously described by Mruwat et al 40 RNA quality was assessed by using 1% agarose gel electrophoresis, then stored at Ϫ80°C for further analysis.…”

“…11,35 This indeed makes physiologic sense in airway conditions because Cys-LTs are bronchoconstrictors, whereas PGE 2 is a bronchodilator. 11,35,40 However, the eicosanoids, as metabolites of AA, are downstream products of the cascade of inflammatory lipid mediators, whereas the upstream PLA 2 action produces both AA and lysophospholipids (Lyso-PL). As discussed in our previous reviews, 16,34 the LysoPLs, although given little attention, play important roles in respiratory pathologies (e.g., lysophosphatidyl serine activates mast cells to secrete histamine 16 ) and, therefore, focusing on eicosanoids as the sole players in these pathologies is in fact misleading.…”

Inhibition of Cytosolic Phospholipase A2α (cPLA2α) by Medicinal Plants in Relation to Their Phenolic Content

“…In addition to the effect in the paw edema model, Urtica dioica extracts were shown to inhibit COX-1 and COX-2 directly and to act as an antagonist at the histamine 1 receptor, a key target for allergic reactions [30,31]. With regard to the role of cPLA2α enzyme in allergic reactions [4,5,6], the cPLA2α inhibiting the potential of Urtica dioica may be important as an anti-allergy agent.…”

“…Among PLA2 enzymes, the cytosolic PLA2 alpha from Subgroup IV (cPLA2α) is known to have the highest specificity for AA [2] and, therefore, is discussed as the key enzyme in the release of AA for eicosanoid synthesis [1,3]. cPLA2α has been associated with inflammation-related diseases, like asthma and allergic reactions [4,5,6], arthritis [7,8] and neuronal diseases, such as Alzheimer’s disease [9,10], multiple sclerosis [11] and Parkinson’s disease [12]. Therefore, the cPLA2α isoform should be a potential target for anti-inflammatory drugs [13].…”