Inhibition of pulmonary inflammatory diseases, asthma and pulmonary fibrosis, by lipoxin A4 and a novel series of selective small molecule FPRL1 agonists

Abstract

Rationale Administration of a lipoxin A4 stable analog blocks airway hyperresponsiveness (AHR) and pulmonary inflammation. The lipoxin A4 receptor, LXA4R/FPRL1, is a G protein-couple receptor expressed on leukocytes. In this study, we examined the effect of lipoxin A4 and a novel series of small molecule FPRL1 agonists on inflammatory responses. Small molecule compounds with an anti-inflammatory profile in vitro were then assessed in animal models of asthma and pulmonary fibrosis in vivo. Methods Eosinophils and neutrophils were incubated with lipoxin A4 or FPRL1 agonists prior to induction of LL37-induced eosinophil degranulation and IL-8 synthesis from neutrophils in response to TNFα. LL37, an antimicrobial peptide, can cause eosinophil degranulation and results in high levels of eosinophil cationic protein (ECP) in cell culture supernatants. In addition, active compounds were further assessed for their ability to inhibit ovalbumin-induced AHR in BALB/c mice and bleomycin-induced pulmonary fibrosis in C57BL/6 mice. Results LL37-induced ECP was suppressed by lipoxin A4 and some receptor specific agonists. Furthermore, AR232925 suppresses ovalbumin-induced AHR in vivo. In neutrophils, TNFα-induced IL-8 was suppressed by lipoxin A4 and several novel FPRL1 agonists. One of these FPRL1 agonists, AR234245, decreased mortality in the mouse model of bleomycin-induced pulmonary fibrosis. Conclusions Here we show that a novel series of selective FPRL1 receptor agonists inhibit eosinophil degranulation and IL-8 responsiveness in neutrophils in vitro. In addition, these agonists inhibit AHR and pulmonary fibrosis in vivo. These data suggest the use of a novel series of FPRL1 agonists for the treatment of human asthma and COPD.