The unusual regenerative properties of the liver have evolved as an efficient adaptation that allows thisorgan to cope with many hazardous conditions, including alcoholism, drug overdose, and viral hepatitis.Recent studies in our laboratory have demonstrated the involvement of complement in the primingphase of liver regeneration. The regenerative response is impaired after partial hepatectomy (PHx) andcarbon tetrachloride (CCI4) injury in several mouse strains deficient in complement components.Impairment of regeneration has been demonstrated by a decreased and delayed replication rate of livercells. Moreover, complement deficiencies have been associated with significant injury to the liverparenchyma after PHx. Our recent data indicate that complement deficiency alters the cytokine milieuafter PHx, including cytokines essential for liver cell proliferation and survival. Therefore, wehypothesize that complement proteins are involved in the regulation of two cellular processes crucial forsuccessful regeneration: proliferation of liver cells and hepatoprotection. The current researchproposal aspires to elucidate the role of complement components in cell proliferation and survival usingthe PHx model, and to determine the effect of therapeutic interventions involving the complementsystem on tissue injury induced by CCI4. The studies in Aim 1 are designed to define the role ofindividual complement components in cell proliferation and hepatoprotection after PHx. This goal will beachieved by disrupting complement signaling pathways after PHx using mice deficient in variouscomplement components, then monitoring liver cell proliferation and injury. The studies in Aim 2 willdissect the mechanisms by which complement components influence liver cell proliferation and survivalafter PHx. The serum levels of cytokines known to be essential for liver cell proliferation and survival,together with their downstream targets in the liver, will be analyzed in mice deficient in complementproteins, tin addition, the role of anaphylatoxins in liver regeneration-associated angiogenesis will beinvestigated.** Finally, the research described in Aim 3 is designed to ascertain whether therapeuticinterventions involving the complement system will decrease the magnitude of tissue injury resultingfrom CCI4-mediated toxicity. The proposed studies should lead to a better understanding of therelationship between regulatory molecules of inflammation and cell proliferation and death, two cellularprocesses essential for physiology and pathology.
Showing the most recent 10 out of 226 publications
