This proposal represents a highly integrated examination of the mechanisms by which injured tissue elicits a response from the host and one of the harmful effects of this response. Data which from our past study of the complement pro-inflammatory serum protein system suggests that, in many circumstances, the complement responses causes more of an injury than the original insult itself. Accordingly, inhibition of complement has led to a diminution in the degree of final injury. Therefore, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish to (1) understand the mechanism by which injured tissue activates the inflammatory response, (2) understand the sequence of events leading from the injury's local injured tissue to the inflammatory attack directed against it, (4) to compare the inflammatory response to injury to the response generated by other insults, and (5) synthesize these data to produce an effective therapeutic strategy to reduce the degree of tissue damage which results from a specific injury occurrence. The Trauma Center Core will provide the forum with which to focus the group of four investigators in their examination of the interrelationship of complement with antibodies and tissue metabolism. by utilizing shared animal models, assays, facilities, and intellects. Project one will relate changes in cellular energetics and membrane metabolism to indicators of inflammatory attack utilizing NMR technology in models of ischemia and reperfusion injury. Project two will assess the interplay of serum complement and lymphocyte natural antibody repertoire in the production of post-injury inflammation. The third project will investigate both novel methods of complement inhibition and the interaction of local injury with remote injury. The fourth project will assess changes in injured tissue membrane proteins with a goal of antibody based therapy. By this funding mechanism, we wish to efficiently and by multiple techniques assess the veracity of our primary hypothesis and to postulate therapies more specific than global inhibition of serum complement.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM052585-06
Application #
6181147
Study Section
Special Emphasis Panel (ZGM1-TB-4 (01))
Program Officer
Somers, Scott D
Project Start
1995-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
6
Fiscal Year
2000
Total Cost
$1,142,678
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Sadeghipour, Hamed; Torabi, Radbeh; Gottschall, James et al. (2017) Blockade of IgM-Mediated Inflammation Alters Wound Progression in a Swine Model of Partial-Thickness Burn. J Burn Care Res 38:148-160
Sheu, Eric G; Wakatsuki, Kohei; Oakes, Sean et al. (2016) Prevention of intestinal ischemia-reperfusion injury in humanized mice. Surgery 160:436-42
Bankova, L G; Dwyer, D F; Liu, A Y et al. (2015) Maturation of mast cell progenitors to mucosal mast cells during allergic pulmonary inflammation in mice. Mucosal Immunol 8:596-606
Dwyer, Daniel F; Woodruff, Matthew C; Carroll, Michael C et al. (2014) B cells regulate CD4+ T cell responses to papain following B cell receptor-independent papain uptake. J Immunol 193:529-39
Bankova, Lora G; Lezcano, Cecilia; Pejler, Gunnar et al. (2014) Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions. J Immunol 192:2812-20
Houde, Martin; Jamain, Marc-David; Labonte, Julie et al. (2013) Pivotal role of mouse mast cell protease 4 in the conversion and pressor properties of Big-endothelin-1. J Pharmacol Exp Ther 346:31-7
Gurish, Michael F; Austen, K Frank (2012) Developmental origin and functional specialization of mast cell subsets. Immunity 37:25-33
Younan, George J; Heit, Yvonne I; Dastouri, Pouya et al. (2011) Mast cells are required in the proliferation and remodeling phases of microdeformational wound therapy. Plast Reconstr Surg 128:649e-58e
Afnan, Jalil; Ahmadi-Yazdi, Cyrus; Sheu, Eric G et al. (2010) Inhibition of rat gut reperfusion injury with an agent developed for the mouse. Evidence that amplification of injury by innate immunity is conserved between two animal species. Am J Physiol Regul Integr Comp Physiol 298:R1675-81
Haas, Michael S; Alicot, Elisabeth M; Schuerpf, Franziska et al. (2010) Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction. Cardiovasc Res 87:618-27

Showing the most recent 10 out of 34 publications