Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Abstract

Rationale: Secreted phospholipase A 2 enzymes (sPLA 2 s) play key regulatory roles in the biosynthesis of eicosanoids, such as the cysteinyl leukotrienes, but the role of these enzymes in the pathogenesis of asthma is not known. Objectives: To establish if sPLA 2 s are overexpressed in the airways of patients with asthma, and to determine if these enzymes may play a role in the generation of eicosanoids in exercise-induced bronchoconstriction. Methods: Induced sputum samples were obtained from subjects with asthma with exercise-induced bronchoconstriction and nonasthmatic control subjects at baseline, and on a separate day 30 minutes after exercise challenge. The expression of the PLA 2 s in induced sputum cells and supernatant was determined by quantitative polymerase chain reaction, immunocytochemistry, and Western blot. Measurements and Main Results: The sPLA 2 s expressed at the highest levels in airway cells of subjects with asthma were groups X and XIIA. Group X sPLA 2 (sPLA 2 -X) was differentially overexpressed in asthma and localized to airway epithelial cells and bronchial macrophages. The gene expression, immunostaining in airway epithelial cells and bronchial macrophages, and the level of the extracellular sPLA 2 -X protein in the airways increased in response to exercise challenge in the asthma group, whereas the levels were lower and unchanged after challenge in nonasthmatic control subjects. Conclusions: Increased expression of sPLA 2 -X may play a key role in the dysregulated eicosanoid synthesis in asthma.

Blockade of Human Group X Secreted Phospholipase A2 (GX-sPLA2)-induced Airway Inflammation and Hyperresponsiveness in a Mouse Asthma Model by a Selective GX-sPLA2 Inhibitor

“…The levels of GXsPLA 2 , but not GIIA-sPLA 2 , correlated with asthma severity, airway inflammation (sputum neutrophils), and eicosanoid release (BAL fluid prostaglandin E 2 ); greater expression of GX-sPLA 2 compared with other sPLA 2 s (GIIA-sPLA 2 and GV-sPLA 2 ) was also detected in the airway epithelia of the asthmatics (17). We previously found that GX-sPLA 2 was differentially overexpressed in the airway cells (airway epithelial cells and bronchial macrophages) of subjects with asthma and exercise-induced bronchoconstriction compared with other human sPLA 2 s, with further increase in the airways of GX-sPLA 2 in these subjects after exercise challenge (9). Genome-wide expression profiling of this group of asthmatics with exercise-induced bronchoconstriction compared with asthmatic individuals without exercise-induced bronchoconstriction demonstrated that TGM2 (transglutaminase 2) was the gene most differentially expressed at base line between these two groups of asthmatics, with increased expression of TGM2 found in airway epithelial brushing from the asthmatics with exercise-induced bronchoconstriction compared with non-asthmatic control subjects (18).…”

Deficiency of Phospholipase A2 Receptor Exacerbates Ovalbumin-Induced Lung Inflammation

“…These higher levels were associated with greater levels of eicosanoids and Th2 cytokines in BALF from PLA 2 R 2/2 mice than from PLA 2 R +/+ mice. Previous animal and human studies showed that sPLA 2 have an important role in the genesis of airway inflammation through the production of proinflammatory eicosanoids in a variety of inflammatory cells (11)(12)(13)(14)(15). Eicosanoids including CysLTs, LTB 4 , and PGD 2 cause lung inflammation directly or indirectly through induction of Th2 cytokines (1)(2)(3)(4).…”

“…Previous in vitro studies have demonstrated that sPLA 2 -IB and sPLA 2 -X are internalized and degraded via the lysosomal pathway after their binding to PLA 2 R, implicating a possible role of the receptor in the clearance of extracellular sPLA 2 (18)(19)(20)(21)(22). sPLA 2 -IB and sPLA 2 -X are expressed in the lung (11,12,23). The animal study using sPLA 2 -X-deficient mice showed that sPLA 2 -X produced proinflammatory eicosanoids and Th2 cytokines and played a critical role in genesis of allergen-induced airway inflammation (12).…”

“…These eicosanoids are 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acids, and the cellular availability of arachidonic acid is tightly controlled by hydrolysis of membrane phospholipids via the catalytic activity of phospholipases A 2 (PLA 2 ) (5-10). Previous animal and human studies showed that PLA 2 is involved in the genesis of airway inflammation through proinflammatory eicosanoids (11)(12)(13)(14)(15).…”

“…The animal study using sPLA 2 -X-deficient mice showed that sPLA 2 -X produced proinflammatory eicosanoids and Th2 cytokines and played a critical role in genesis of allergen-induced airway inflammation (12). The human study indicated that sPLA 2 -X could have a role in the generation of proinflammatory eicosanoids in the airways, leading to the development of bronchial hyperresponsiveness (11). In addition, sPLA 2 -IB was found to elicit the production of proinflammatory eicosanoids in the lung and the contraction of airway smooth muscles (24).…”