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Thermal tolerance of skeletal muscle and small intestine: role of eicosanoid metabolism and oxidative stress

Oliver, Scott Ryan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1253192991

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Biophysics.
This research investigated the thermal tolerance (i.e. the highest temperature which does not cause dysfunction) of skeletal muscle and the small intestine and evaluated the effects of inhibiting eicosanoid metabolism and oxidative stress. Skeletal muscle is a primary source of heat in exertional hyperthermia and loss of intestinal barrier function is considered a critical event in the pathogenesis of heat stroke. A mechanism of hyperthermia-induced dysfunction in these organ systems is poorly understood.Contractile function was measured in rat diaphragm during and after 30 min exposure to 40 to 43° C. Only at 43° C, a significant loss of active force was observed. Lipoxygenase inhibitors (baicalein and eicosatetreanoic acid) as well as cyclooxygenase inhibitors (ibuprofen and indomethacin) further depressed the loss of function at 43° C and induced a loss of thermal tolerance at 42° C. Treatment of diaphragm muscle with reactive oxygen species (ROS) scavengers, tiron and Trolox, did not inhibit the loss of contractile force at 43° C, suggesting that the ROS that are affected by these scavengers are not involved. Blockage of phospholipase A2, causing a decrease in the enzymatic substrate for eicosanoid metabolism, was unable to prevent the loss of contractile force at 43° C. Mouse small intestine permeability was monitored using a modified everted gut protocol. Tissues were exposed to 37° C to 42.5° C for 90 minutes and permeability was assessed using the diffusion of a fluorescent molecule (4 kDa simulating the permeability of molecules the size of endotoxin) into the everted gut sacs. At 40.5° C, intestinal permeability remained unchanged, but increased significantly when exposed to higher temperatures. Treatment with baicalein, indomethacin or the antioxidant N-acetyl cysteine (NAC) significantly protected permeability at 41.5° C. Protein carbonyl levels were used as a marker of cellular oxidative stress and increased after 90 minutes of 41.5° C exposure. Hyperthermia also significantly increased structural damage as measured by microscopy. Baicalein and NAC both reduced protein oxidation, but only NAC reduced structural damage. This suggests that ROS could play a major role in hyperthermia-induced barrier dysfunction. The mechanism for the increase in intestinal permeability was studied using compounds known to induce opening of tight junctions to compare to permeability observed during hyperthermia. Cytochalasin D was the only compound that increased intestinal permeability at 37° C as measured by a 0.48 kDa probe. However, it resulted in severe structural damage to the epithelial cells. Despite the observed structural damage, opening of tight junctions did not cause enough permeability to explain all observations during hyperthermia. Lactate dehydrogenase, a marker for cell cytotoxicity, was found to increase during hyperthermia at 30 and 60 min. The results are consistent with cell damage being the predominant cause of increased intestinal permeability during hyperthermia, most likely mediated by ROS. However, in skeletal muscle a completely different mechanism appears actively involved. Both antioxidants and/or lipoxygenase inhibitors such as baicalein show potential for ameliorating morbidity of heat stroke.
Mark Wewers (Advisor)
Mark Angelos (Committee Member)
Gunjan Agarwal (Committee Member)
Govindasamy Ilangovan (Committee Member)
197 p.
Anatomy and Physiology; Animals
Skeletal muscle; small intestine; hyperthermia; heat stress; eicosanoid metabolism; lipoxygenase; cyclooxygenase

Recommended Citations

Citations

  • Oliver, S. R. (2009). Thermal tolerance of skeletal muscle and small intestine: role of eicosanoid metabolism and oxidative stress [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1253192991

    APA Style (7th edition)

  • Oliver, Scott. Thermal tolerance of skeletal muscle and small intestine: role of eicosanoid metabolism and oxidative stress. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1253192991.

    MLA Style (8th edition)

  • Oliver, Scott. "Thermal tolerance of skeletal muscle and small intestine: role of eicosanoid metabolism and oxidative stress." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1253192991

    Chicago Manual of Style (17th edition)

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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.