Abstract
The Glu-Leu-Arg (ELR+) chemokines (e.g., CXCL8/IL-8, CXCL1/GROα) play an important role in neutrophilic inflammation through binding to two distinct G protein-coupled receptors (GPCR), the CXCR1 and CXCR2. We have generated a potent human ELR+CXC chemokine antagonist, CXCL8(3–72)K11R/G31P (hG31P), which blocks neutrophil chemotaxis and intracellular calcium mobilization induced by the ELR+CXC chemokines. We report herein that hG31P also antagonizes acute lung injury induced by lipopolysaccharide, >95% reducing neutrophil infiltration into, and activation within, the airways, as determined by direct counting and assays of neutrophil granule markers (i.e., myeloperoxidase, lactoferrin, and MMP-9). This hG31P also antagonized chemotaxis and calcium mobilization responses induced in neutrophils by C5a, LTB4 and fMLP, which signal via alternate GPCR. Moreover, hG31P dose-dependently inhibited the expression of CXCL1 and CXCL8 by LPS-challenged A549 human airway epithelial cells, and reversed the anti-apoptotic effects of ELR+CXC chemokines on neutrophils. These data indicate that ELR+CXC chemokine antagonism targets inflammatory responses at multiple levels, through actions on epithelial cells, neutrophils, and heterologous GCPR. (Research supported by funds from CIHR, NSERC and IL Therapeutics)
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