Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response.
The role of complement component C5 in asthma remains controversial. Here we examined the contribution of C5 at 3 critical checkpoints during the course of disease. Using an mAb specific for C5, we were able to evaluate the contribution of C5 during (a) the initiation of airway inflammation, (b) the maintenance of airway hyperresponsiveness (AHR), and (c) sustainment of an ongoing airway response to allergen provocation. Our results indicate that C5 is probably activated intrapulmonarily after infections or exposures to allergen and C5 inhibition has profound effects at all 3 critical checkpoints. In contrast to an earlier report, C5-deficient mice with established airway inflammation did not have elevated AHR to nonspecific stimuli. In the presence of airway inflammation, C5a serves as a direct link between the innate immune system and the development of AHR by engaging directly with its receptors expressed in airways. Through their powerful chemotactic and cell activation properties, both C5a and C5b-9 regulate the downstream inflammatory cascade, which results in a massive migration of inflammatory cells into the bronchial airway lumen and triggers the release of multiple harmful inflammatory mediators. This study suggests that targeting C5 is a potential clinical approach for treating patients with asthma.
Peng
Tao
T
Alexion Pharmaceuticals Inc., Cheshire, Connecticut 06410, USA.
Hao
Liming
L
Madri
Joseph A
JA
Su
Xiao
X
Elias
Jack A
JA
Stahl
Gregory L
GL
Squinto
Stephen
S
Wang
Yi
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D001980:Bronchi / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology
D000911:Antibodies, Monoclonal; D015938:Complement Membrane Attack Complex; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a