Mechanisms of intestinal mucosa damage as therapeutic targets in postburn sepsis

Dr. Walid Al-Ghoul
Department of Biological Sciences

 

Dr. Walid Al-Ghoul

Sepsis is the main cause of death in severe burn and trauma patients with an estimated yearly toll of three quarter million illnesses and 215 The pathogenesis of postburn sepsis is preceded by an overwhelming immune response, namely, systemic inflammatory response syndrome (SIRS),

 

 

thousand deaths in the USE alone and associated with a protracted immune suppression, termed, compensatory anti-inflammatory response syndrome (CARS). SIRS is associated with hyperactivation of neutrophils and other injurious events that are thought to cause subsequent tissue damage and immunosuppression. My central hypothesis is that SIRS involves neutrophil hyperactivation and the release of injurious factors that converge not only at the level of the intestinal epithelial cell barrier but also associated immune cells, thus contributing to CARS and sepsis. My objective is to define SIRS-related injurious factors and assess them as possible targets for therapeutic intervention to prevent the pathogenesis of sepsis.

The rationale for the proposed work is that specific steps in sepsis pathogenesis lend themselves to the actions of drugs that have already been explored in other systems, preliminarily, statins and poly(ADP-ribose) polymerase (PARP) inhibitors. The expected outcome of this work is (1) that targeted pharmaceutical interventions will have been assessed against postburn intestinal barrier dysfunction, which had been dubbed as the cause of turning the epithelial barrier into a “motor” supplying sepsis, and (2) that early therapeutic intervention against neutrophils and their injurious agents will have been compared with later interventions against postburn mechanisms of dysfunction within intestinal epithelial cells as well as mesenteric lymph node T cells. Such an outcome is expected to have a substantive impact on our understanding of postburn sepsis and could ultimately provide proven pharmaceutical interventions applicable to health-care management of severe burn patients in order to minimize postburn sepsis-related morbidity and mortality.

RECENT PUBLICATIONS

Nadeem Fazal, Syed Raziuddin, Mehdi Khan and Walid M. Al-Ghoul (2006) Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat. Biochim Biophys Acta. 2006 Jan;1762(1):46-53.

Fazal N, Raziuddin S, Khan M, Al-Ghoul WM. Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat. Biochim Biophys Acta. 2005 Nov 30;1762(1):46-53. Epub 2005 Oct 11.

Al-Ghoul WM, Khan M, Fazal N, Sayeed MM. Mechanisms of postburn intestinal barrier dysfunction in the rat: roles of epithelial cell renewal, E-cadherin, and neutrophil extravasation. Crit Care Med. 2004 Aug;32(8):1730-9.

Kotadia BK, Ravindranath TM, Choudhry MA, Haque F, Al-Ghoul WM, Sayeed MM. Effects of pentoxyfylline on mesenteric lymph node T-cells in a rat model of thermal injury. Shock. 2003 Dec;20(6):517-20.

Choudhry MA, Haque F, Khan M, Fazal N, Al-Ghoul WM, Ravindranath T, Gamelli RL, Sayeed MM.  Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury. Crit Care Med. 2003 Jun;31(6):1764-70.

Goto M, Samonte V, Khan M, Haque F, Goyal A, Al-Ghoul WM, Raziuddin S, Fazal N, Ravindranath T, Reed RL, Gamelli RL, Sayeed MM.  Enterococcus faecalis exacerbates burn injury-induced host responses in rats. Shock. 2002 Dec;18(6):523-8.

Fazal N, Al-Ghoul WM, Schmidt MJ, Choudhry MA, Sayeed MM.  Lyn- and ERK-mediated vs. Ca2+ -mediated neutrophil O responses with thermal injury. Am J Physiol Cell Physiol. 2002 Nov;283(5):C1469-79.

Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, Krause DN.  MT(2) melatonin receptors are present and functional in rat caudal artery.  J Pharmacol Exp Ther. 2002 Sep;302(3):1295-302.

RECENT PRESENTATIONS

(RISE students are indicated in boldface.)

Rachele Hendricks, Charles Hollins, Byeong Gyu Park, Nadeem Fazal, Walid Al-Ghoul, “Inflammation-Mediated Damage in the Gut Following Thermal Injury in Rats”. Minority Trainee Research Forum, Sunny Isles Beach, Florida, September 7-10, 2006.

Rachele Hendricks, Byeong-Gyu Park, Nadeem Fazal, Walid Al-Ghoul. Inflammation-Mediated Damage in Gut Epithelium Following Thermal Injury in Rats. The 17th Annual Illinois Student Research Conference, Eastern Illinois University, Charleston, IL; March 23-24,2006.

Charles Hollins, Abdulraman El-Arja, Steve Abu Shaqra, Byeong-Gyu Park, Nadeem Fazal, Walid Al-Ghoul. Metabolic Profiles and Intestinal Permeability Changes After Thermal Injury With and Without Early Anti-Inflammatory Treatment in Rats. The 17th Annual Illinois Student Research Conference, Eastern Illinois University, Charleston , IL; March 23-24,2006.

Andre Wimberly, Nazmy Hamad, and Walid Al-Ghoul. Possible Immune Mechanisms of Intestinal Pathology after Major Skin Thermal Stress and Their Therapeutic Implications. 2005 LS-AMP symposium, Oakbrook, IL, March 2005.

Kafayat Davies, Nazmy Hamad, Nadeem Fazal and Walid Al-Ghoul. Microscopic And Macroscopic Evidence Of Gut Leakiness After Major Thermal Dermal Stress. The 16th Annual Illinois Student Research Conference; Oakbrook, IL; March 2005.

Andre Wimberly, Booker Davis, Rachelle Hindricks, Boriana Tschernookiova, Kafayat Davies, and  Walid Al-Ghoul. Inflammatory Events Involved in Intestinal Pathology after Major Skin Thermal Stress.   ISAS annual conference, Knox College, April 2005.

Walid Al-Ghoul, et. al.(2004) Mechanisms of Post-Burn Intestinal Barrrier Dysfunction in the Rat: Roles of Epithelial cell Renewal, E-Cadherin and neurophil Extravasalation. Critical Care Medicine, 32(8): 1730-9.

Booker T Davis IV and Walid M. Al-Ghoul. Intestinal Permeability Increase After Major Skin Thermal Injury Is Preventable By Early Treatment With Simvastatin. 2004 Annual Biomedical Research Conference for Minority Students (ABRCMS); Dallas, Texas; November 10-13, 2004.

Michelle E. Stewart and Walid M. Al-Ghoul. Inflammation-Related Tissue Damage In Mesenteric Lymph Nodes: Benefits Of Early Intervention With Statins. 2004 Annual Biomedical Research Conference for Minority Students (ABRCMS); Dallas, Texas; November 10 - 13, 2004.

Dr.Al-Ghoul and his students
Dr. Al-Ghoul (extreme right) and his MBRS-RISE Program research students

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