Preclinical Evaluation of an Inhibitor of Cytosolic Phospholipase A₂α for the Treatment of Asthma

Abstract

Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA 2

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…8, B-D), which raises the possibility of its cPLA 2 ␣ dependence, as we have shown previously in A549 cells (25). Currently, a preclinical evaluation study of a cPLA 2 ␣ inhibitor in asthma treatment has been published, showing promising results using various in vitro and in vivo approaches (78). COX2 inhibitors are well known drugs used in prevention of various tumors (79).…”

Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi

“…Although the response of isolated human ASM may not always be identical to that elicited in vivo, isolated airway preparations provide a suitable, convenient, and reproducible biological model for the evaluation of drug effects on ASM independent from the potential systemic influences found in vivo (Endoh and Hori, 2006;Iglarz et al, 2008). In particular, the configuration of the smooth muscle bundles is largely preserved in human isolated bronchi and therefore the bronchial contraction is directly related to airway narrowing Cazzola et al, 2011Cazzola et al, , 2012Hewson et al, 2012;Hulsmann and de Jongste, 1993;Matera et al, 2005Matera et al, , 2008Matera et al, , 2009Matera et al, , 2011aMatera et al, , 2011bRogliani et al, 2013).…”

Neutrophil-Derived Cytosolic PLA2α Contributes to Bacterial-Induced Neutrophil Transepithelial Migration

“…Additionally, cPLA2α has been suggested to play a role in pulmonary fibrosis, as cPLA2α deficient mice are protected from the inflammatory response and fibrosis brought on by bleomycin exposure(33). Pre-clinical studies have assessed the effect of a cPLA2α inhibitor, PF-5212372, on animal models of allergic asthma, but have not considered neutrophilic responses(54, 55). Therefore, cPLA2α has been shown to play a role in the pulmonary disease, but a precise mechanism of action has not been described.…”