title: Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthma.
abstract: Allergic asthma is a chronic inflammatory airway disease arising from an aberrant immune response following exposure to environmental stimuli in genetically susceptible persons. The complement component 5 (C5)/C5a Receptor (C5aR/CD88) signaling pathway has been implicated in both experimental allergic asthma and human asthmatic disease. Targeting the C5a/C5aR signaling pathway in rodent models has been shown to either enhance or reduce allergic asthma consequences. Treatment with a recombinant humanized monoclonal antibody directed against C5 has shown unclear results in patients with asthma. The objective of this proof-of-concept animal study was to determine whether the low molecular weight C5aR peptidomimetic antagonist, PMX205, would reduce experimental allergic asthma consequences in mice. PMX205 or vehicle control was administered subcutaneously to BALB/c mice prior to and during standard ovalbumin (OVA) allergen sensitization and aerosolized challenge phases. PMX205 substantially reduced OVA-induced total cell (60%), neutrophil (66%) and eosinophil (65%) influxes in lavage fluid sampling. There were also significant reductions in OVA-induced lavage fluid IL-13 protein and lung Th2 cytokine gene expression with PMX205 administration. PMX205 treatment also diminished OVA-induced lung parenchyma cellular infiltration. PMX205 administration did not reduce OVA-induced serum IgE levels or epithelial mucous/goblet cell generation. There was no evidence of toxicity observed with PMX205 treatment in saline or OVA-challenged animals. These data provide evidence that pharmacologic blockade of C5aR by a low molecular weight antagonist (PMX205) reduces airway inflammatory cell and cytokine responses in experimental allergic asthma, and suggests that PMX205 might represent a novel therapeutic agent for reducing asthmatic outcomes.
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, 985990 Nebraska Medical Center, Omaha, NE 68198-5990, United States.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Staab
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, United States.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Sanderson
authors.affiliation: Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN 55414, United States.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Wells
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, 985990 Nebraska Medical Center, Omaha, NE 68198-5990, United States. Electronic address: japoole@unmc.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Poole
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000485:Allergens; D018793:Interleukin-13; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: Allergy; Asthma; C5a receptor; Complement; Inflammation; Therapy