Secondary bacterial peritonitis continues to be a difficult problem for both patient and surgeon. Even with the advent of newer antibiotics, little improvement in mortality has been achieved. Within the internal milieu of the peritoneal cavity, host defense mechanisms normally should act to limit the growth and dispersion of invading microorganisms. We seek to obtain a better understanding of these host defenses both at the cellular level as well as in the entire animal. In particular, the aims of this grant are 1) to define the mechanism of the potentiating effect of hemoglobin in experimental peritonitis, 2) to determine the specific action of fibrinogen and fibrin in experimental peritonitis and intraperitoneal abscess formation. In the first case, the present evidence supports the idea that hemoglobin permits certain strains of E. coli to elaborate leukotoxins which inhibit the bacteriocidal function of neutrophils and monocytes. This, in turn, permits the bacteria to proliferate to lethal levels. In the second, fibrin and its breakdown products impair the bacteriocidal function of neutrophils and monocytes by a different mechanism, i.e. by impairing access to the bacteria by limiting the migration of host cells into contact with bacteria. To test these hypotheses, both in vivo and in vitro techniques will be necessary. For the first aim, the basic strategy is to isolate and characterize those products of the interaction between bacteria and hemoglobin which impair neutrophil function in vitro. These materials will then be tested in rats for their capacity to potentiate infections with bacterial strains which cannot be potentiated with hemoglobin itself. For the second aim, we plan to differentiate between the physical entrapment of neutrophils by fibrin, its chemical effects on the neutrophil and its alteration of the physiological milieu.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Wang, Jin; Grishin, Anatoly V; Ford, Henri R (2016) Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96. J Immunol 196:5130-7
Grishin, Anatoly; Bowling, Jordan; Bell, Brandon et al. (2016) Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 51:13-7
Al Alam, Denise; Danopoulos, Soula; Schall, Kathy et al. (2015) Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine. Am J Physiol Gastrointest Liver Physiol 308:G678-90
McElroy, Steven J; Castle, Shannon L; Bernard, Jessica K et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 184:2768-78
Papillon, Stephanie; Castle, Shannon L; Gayer, Christopher P et al. (2013) Necrotizing enterocolitis: contemporary management and outcomes. Adv Pediatr 60:263-79
Ford, Henri R; Hackam, David J (2013) Management of premature infants. Preface. Semin Pediatr Surg 22:67-8
Grishin, Anatoly; Papillon, Stephanie; Bell, Brandon et al. (2013) The role of the intestinal microbiota in the pathogenesis of necrotizing enterocolitis. Semin Pediatr Surg 22:69-75
Short, Scott S; Wang, Jin; Castle, Shannon L et al. (2013) Low doses of celecoxib attenuate gut barrier failure during experimental peritonitis. Lab Invest 93:1265-75
Liu, Quin; Mittal, Rahul; Emami, Claudia N et al. (2012) Human isolates of Cronobacter sakazakii bind efficiently to intestinal epithelial cells in vitro to induce monolayer permeability and apoptosis. J Surg Res 176:437-47
Emami, Claudia N; Mittal, Rahul; Wang, Larry et al. (2012) Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii. J Surg Res 172:18-28

Showing the most recent 10 out of 92 publications