This proposal represents a continuing highly integrated examination of the mechanisms by which injured tissue elicits a response from the host and of the harmful effects of this response. Data derived from our past studies of the complement pro-inflammatory serum protein system suggests that, in model reperfusion injury of several organs, the complement response causes more of an injury than the original ischemic insult itself. Accordingly, inhibition of complement activation by a variety of means or in a variety of genetically modified mice has produced a diminution in the degree of final injury. Therefore, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish (1) to understand the mechanism by which injured tissue activates the inflammatory response, (2) to understand the specific sequence of events leading from an ischemic insult to inflammatory activation, (3) to modify the antibody-binding component of the immune system activation caused by reperfusion injury, (4) to fully characterize human reperfusion injury and attempt to ameliorate it with the knowledge gained from this grant to date, and (5) to 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 (Project I) will provide the financial support for the knock-out mice used by 3 of the projects, the data support for the clinical project, and the administrative support for the overall grant and its outreach programs. Project II will use techniques of molecular biology to identify potential neoantigens on injured tissue. Project III will investigate and modify a range of murine B1 cell natural antibody clones to fully define the role of natural antibody in reperfusion injury. Project IV will investigate the role of mast cell degranulation in the genesis of reperfusion injury and resulting complement activation. Project V will characterize human mesenteric reperfusion injury utilizing newly available techniques. By this funding mechanism, we wish to efficiently, and by multiple techniques, arrive at specific therapy for mesenteric reperfusion injury, the related injury of other organ systems, and an avenue of prevention for organ failure following massive traumatic injury and its accompanying shock.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM052585-12
Application #
7124214
Study Section
Special Emphasis Panel (ZGM1-TB-6 (01))
Program Officer
Somers, Scott D
Project Start
1995-04-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
12
Fiscal Year
2006
Total Cost
$1,200,410
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
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