phys

The major aims are to investigate the mechanism of action of IL-1, an inflammatory cytokine, on the regulation of intestinal epithelial cell function. The role of phospholipase A2 and PLA2-activating protein (PLAP) in mediating the effect(s) of IL-1 on ion transport and their role in inflammation will be evaluated. The specific aims of the project include: 1) The identification and characterization of the IL-1 receptor on epithelial cells; 2) The involvement of PLA2, PLAP, and cyclooxygenase (Cox) isoenzymes and second messengers like Ca2⁺ and cAMP on mediating the effects of IL-1; 3) Regulation of these mediators by IL-1; 4) Localization of IL-1 receptor and of PLAP and Cox-isoenzymes; and 5) Using a rabbit model of colitis, the role of IL-1b on epithelial function is assessed and compared to normal tissue. The activity of PLA2, levels of PLAP and the levels of the isoenzymes Cox-1 and Cox-2 are measured. F. R. Homaidan.

Adhesion and gap junctional communication between macrophages and intestinal epithelial cells

In intestinal inflammation, inflammatory cell infiltrates are found juxtaposed to the epithelial cell basolateral membranes. We have shown that specific adhesion occurs between macrophages and intestinal epithelial cells (IEC). This adhesion was only partially dependent on the macrophage b 2-integrin. The study is conducted to determine if IEC and inflammatory cells, mainly macrophages (Mf ), interact and communicate. Labeled Mf adhered specifically and transferred dye to Mode-K, an IEC cell line. Calcein dye transfer was bi-directional and strictly adhesion dependent, a characteristic of gap junctional coupling. Both homo- and heterocellular dye transfer in co-cultures of IEC and/or macrophages are detected, and are inhibited by heptanol. Propagation of calcium waves (studied by confocal microscopy) between IEC, and between IEC and adherent Mf indicated communication via gap junctions. The interaction between IEC and macrophages through gap junctions could provide a means by which inflammatory cells regulate IEC function. F.R. Homaidan.

Electrophysiological evidence is gathered in the search for a dorsal column input(s) into various brainstem nuclear groups involved in pain inhibition. This work appears to give further support to our hypothesis about the existence of a dorsal column-brainstem-spinal loop playing a role in pain modulation. S.J. Jabbur, S.F. Atweh and N.D. Saadé. (Supported by LNCSR.)

Our knowledge of the mechanisms involved in the regulation of water, ions and nutrient absorption across thintestinal epithelium has been substantially refined over the past two decades. It is well known now that extrinsic as well as intrinsic innervation of the gut plays a major role in regulating water and ion transport. The possibility that specific nerves and their neurotransmitters can modulate intestinal nutrient absorption has not been well defined. The aim of the study is to evaluate the involvement of the vagus nerve and more specifically the vagal capsaicin-sensitive primary afferent fibers in regulating amino acid transport across intestinal epithelia. Such regulation can be thruough a sequence of events in neural pathways that would lead to stimulation or inhibition of nutrient absorption, or due to the release of one or more of the neuropeptides and/or neurotransmitters that could mediate the neural input in the absorptive function of the small intestine. C.F. Nassar, K.A. Barada, S.F. Atweh and N.E. Saadé. (Supported by URB.)

In experiments designed to characterize aminoacid transport across myocardial cell membranes, initial data showed inhibition of transport by prostacyclin. Further experiments are being conducted and will investigate other means to enhance and/or inhibit aminoacid transport. Cardiac remodeling in the rat heart subjected to chronic pressure load, and the effect thereon of growth factors and growth inhibitors is being investigated intensively. This model will be used to further characterize aminoacid transport. M.G. Nasser, W. Medawar and H. Kaspar. (Supported by URB; AUB Medical Practice Plan.)

Barada, K.A., Dika, S.S., Atweh, S.F., Saadé, N.E., and Nassar, C.F., Acute and neonatal capsaicin treatment inhibit amino acid absorption through a sodium dependent mechanism. American Journal of Physiology, 272 (Gastrointest. Liver Physiol. 4), G815-G821, 1997.

Martin, C.A.*, El-Sabban, M.E., Zhao, L.*, Burakoff, R.* and Homaidan, F.R., Adhesion and cytosolic dye transfer between macrophages and intestinal epithelial cells. Cell Adhesion and Communication, 5, 1-13, 1997.

Nassar, C.F., Abdallah, L.E., Barada, K.A., Atweh, S.F., and Saadé, N.E., Effects of intravenous vasoactive intestinal peptide injection on jejunal alanine absorption and gastric acid secretion in rats. Regulatory Peptides,55, 261-267, 1995.

Nassar, C.F., Barada, K.A., Abdallah, L.E., Hamdan, W.S., Taha, A.M., Atweh, S.F., and Saadé, N.E, Involvement of capsaicin sensitive primary afferent fibers in regulation of jejunal alanine absorption. American Journal of Physiology, 268 (Gastrointest. Liver Physiol. 31), G695-G699, 1995. This manuscript was reviewed under “Selected Summaries” in Gastroenterology, 110, 315-317, 1996.

Saadé, N.E., Abdallah, L.E., Barada, K.A., Atweh, S.F., and Nassar, C.F., Effects of intracerebral injections of VIP on jejunal alanine absorption and gastric acid secretion in rats. Regulatory Peptides, 55, 269-276, 1995.

Safieh-Garabedian, B., Kanaan, S.A., Jalakhian, R.H., Poole, S., Jabbur, S.J., and Saadé, N.E, Hyperalgesia induced by low doses of thymulin injections: Possible involvement of prostaglandin E₂. Journal Neuroimmunology, 73, 162-168, 1997.

Atweh, S.F., Jabbur, S.J., Bahuth, N.B., and Saadé, N.E., Chemical lesions to brainstem dopaminergic neurons facilitate nociceptive reflexes (NR) and accelerate autotomy (AT) behavior in rats (abstract). Society for Neuroscience, 22, 112, 1996.

Barada, K.A., Dika, S.S., Atweh, S.F., Taha, A.M., Saadé, N.E., and Nassar, C.F., Capsaicin inhibition of alanine absorption in the rat jejunum is neurally mediated and involves a decrease in the affinity for alanine absorption. Gastroenterology, 108, A716, 1995.

Barada, K.S., Saadé, N.E., Atweh, S.F. and Nassar, C.F., Chemical ablation of the intestinal myenteric plexus and its extrinsic innervation reduces alanine absorption in the rat jejunum. Gastroenterology, 110, A730, 1996.

Homaidan, F.R., Martin, C.A.*, and El-Sabban, M.E., Gap junctional communication between macrophages and intestinal epithelial cells. International Meeting on Gap Junctions, Florida, 1997.

Homaidan, F.R., Zhao, L.M.*, and Burakoff, R.*, PGE₂production and regulation by IL-1, PLA₂, PLAP and COX-2 in MODE-K cell line. Annual Meeting of the American Gastroenterological Association, Washington DC, USA, 1997.

Jabbur, S.J., Neural basis of analgesia following dorsal column stimulation, Second International Head and Neck Pain Symposium of the Middle East, sponsored by the Lebanese Dental Association (Fifth Annual Convention) at the Section of Dental Medicine II of the Lebanese University, Beirut, Lebanon, 30 September, 1995.

———, Analgesia, hypalgesia and dorsal column stimulation. Lecture, Neurological Study Unit sponsored by the Department of Physiology and Biophysics, University of Washington, Seattle, USA, December 4, 1995.

———, Neural mechanisms in pain and analgesia, Scientific Basis of Neurology I (#325). Forty-Ninth Annual Meeting of the American Academy of Neurology, 49-67, Boston, USA, April 19, 1997.

Jabbur, S.J., Kanaan, S.A., Safieh-Garabedian, B., Atweh, S.F., and Saadé, N.E., Effects of various drugs on endotoxin (ET)-induced hyperalgesia in rodents (abstracts). Society for Neuroscience, 22, 1812, 1996.

Kanj, N.A., Samaha, M. and Nassar, C.F., Capsaicin inhibits alanine uptake in rat hemidiaphragms in vitro. FASEB Journal, 10 (3), A362, 1996.

Martin, C.A.*, El-Sabban, M.E., Burakoff, R.*, and Homaidan, F.R., Cytokine mediated induction of VCAM-1 expression of MODE-K intestinal epithelial cells. Annual Meeting of the American Gastroenterological Association, Washington DC, USA, 1997.

Martin, C.A.*, El-Sabban, M.E., Palaia, T.*, Burakoff, R.*, and Homaidan, F.R., Gap junctional communication between murine macrophages and intestinal epithelial cell lines. Annual Meeting of the American Gastroenterological Association, Washington DC, USA, 1997.

Melson, S.*, Pianka, J.*, Martello, L.*, Burakoff, R.*, and Homaidan, F.R., Increased PLAP levels and PLA₂ activity in human inflammatory bowel disease. Annual Meeting of the American Gastroenterological Association, Washington DC, USA, 1997.

Nassar, C.F., Barada, K.A., Atweh, S.F. and Saadé, N.E., Inhibition of jejunal alanine absorption by vasoactive intestinal peptide: role of capsaicin sensitive primary afferents. Society for Neuroscience, 21, 1634, 1995.

Safieh-Garabedian, B., Kanaan, S.A., Jabbur, S.J., and Saadé, N.E., Low concentrations of thymulin injection induces hyperalgesia in rats. European Journal of Neuroscience, Suppl. 9, 97, 1996.

Safieh-Garabedian, B., Kanaan, S.A., Jabbur, S.J., Atweh, S.F., and Saadé, N.E., Low doses of thymulin injection in the hindpaw of rats causes localized hyperalgesia (abstract). Society for Neuroscience, 22, 119, 1996.

Taha, A.M., Saadé, N.E., El-Mogharbil, N., Barada, K.A., and Nassar, C.F., Capsaicin specific effect on amino acid absorption in the rat jejunum. FASEB Journal, 9 (3), A368, 1995.

Bitar, H. I., Abnormal metabolic environment versus hemodynamic alterations in the pathogenesis of diabetic induced structural and functional alterations in Sprague-Dawley rats (1997). Advisors: A. Birbari and S. T. Azar.