In this continuation proposal, we seek to expand our understanding of the role of the complement system in chronic lung disease. During the last funding period, we created strains of mice with targeted deletions of the receptors for C5a and C3a anaphylatoxins. Our initial characterizations demonstrated that C5a is intimately involved in lung host defense and acute lung injury, but may demonstrate anti-inflammatory properties as well. Unexpectedly, characterization of the C3a receptor -deficient mice demonstrated a significant role in a model of allergic airways inflammation and bronchial responsiveness. This observation has been subsequently reproduced in guinea pigs and correlative data from humans. By contrast, conflicting data have emerged in mouse and rat studies with C5 and C5a receptor in allergen induced airways hyperresponsiveness. We hypothesize that C3a and C5a are broadly involved in chronic lung diseases, including asthma and bacterial infection, extending beyond neutrophil and macrophage mediated injury to airway epithelium and smooth muscle. In addition, new preliminary data demonstrating up regulation of the cytokine early T cell activator/osteopontin synthesis in bone marrow in response to C5a suggests a mechanistic link between innate and adaptive immunity and may be related to the mechanism of C5a mediated host defense. Significant gaps in our knowledge of the system remain, however. In this renewal, we will address three specific aims.
Aim 1 will investigate the mechanism by which C3a receptor deficiency is protective in models of airways responsiveness.
Aim 2 will address the issue of C5a receptor in the control of allergic airways hyperresponsiveness.
Aim 3 will investigate the C3a and C5a receptors in models of lung defense. Understanding the role of anaphylatoxins in models of lung disease and host defense will provide the proof of principle necessary to advance therapeutics in man.
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