Gastrointestinal ischemia-reperfusion (GI/R) is a common clinical problem in the settings of sepsis hemorrhagic shock, vascular surgery and small bowel transplantation. Complement activation plays an important role in local and remote tissue injury associated with GI/R. Previous work from our lab suggests that the alternative complement pathway is important in amplifying complement activation in GI/R and C5 activation is central to tissue injury. Additionally, several laboratories have recently provided evidence that the terminal complement complex induces apoptosis. However, it is still unclear which complement pathways initiate complement activation and apoptosis following GI/R. In this proposal, we will investigate the role of MBL vs C1q (i.e. lectin vs. classical pathway) during G/JR and determine which complement pathway initiates complement activation following GI/R. We will additionally investigate and target the role of the """"""""key"""""""" complement components MBL, C1q, factor D, C5a and C5b-9. Finally, we will determine which specific complement pathways are involved in G/JR-induced apoptosis following complement activation in vivo in rat and mouse models. We hypothesize that the lectin complement pathway is responsible for the inflammatory process and initiation of apoptosis following G/JR.
The specific aims are as follows: 1) characterize the complement pathways involved in G/JR and 2) determine the role of complement in apoptosis following GI/R.
| Hart, Melanie L; Henn, Martina; Kohler, David et al. (2008) Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury. FASEB J 22:2784-97 |
| Hart, Melanie L; Much, Chressen; Gorzolla, Iris C et al. (2008) Extracellular adenosine production by ecto-5'-nucleotidase protects during murine hepatic ischemic preconditioning. Gastroenterology 135:1739-1750.e3 |
| Hart, Melanie L; Much, Chressen; Kohler, David et al. (2008) Use of a hanging-weight system for liver ischemic preconditioning in mice. Am J Physiol Gastrointest Liver Physiol 294:G1431-40 |
| McMullen, Meghan E; Hart, Melanie L; Walsh, Mary C et al. (2006) Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology 211:759-66 |
| Hart, Melanie L; Ceonzo, Kathleen A; Shaffer, Lisa A et al. (2005) Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 174:6373-80 |
