ELR+CXC Chemokine Antagonist Targets Neutrophilic Pathology at Multiple Levels

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 )