PATHOGENESIS AND TREATMENT OF EXPERIMENTAL PERITONITIS

Project: Research project

Description

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.
StatusFinished
Effective start/end date4/1/781/31/16

Funding

  • National Institutes of Health: $360,000.00
  • National Institutes of Health: $250,148.00
  • National Institutes of Health: $250,690.00
  • National Institutes of Health: $356,400.00
  • National Institutes of Health: $259,372.00
  • National Institutes of Health: $249,712.00
  • National Institutes of Health: $251,747.00
  • National Institutes of Health: $126,270.00
  • National Institutes of Health: $335,016.00
  • National Institutes of Health: $356,400.00
  • National Institutes of Health: $356,400.00

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Peritonitis
Enterocytes
Dinoprostone
Cyclooxygenase 2
Therapeutics
Endotoxemia
src-Family Kinases
Myosin-Light-Chain Kinase
Inflammatory Bowel Diseases
Intestinal Mucosa
Apoptosis
Inflammation
Bacterial Translocation
Focal Adhesion Protein-Tyrosine Kinases
rho-Associated Kinases
Stress Fibers
rho GTP-Binding Proteins
Necrotizing Enterocolitis
Peroxynitrous Acid
Tight Junctions