Cellular mechanisms of burn-related changes in contractility and its prevention by mesenteric lymph ligation

Abstract

Major burn injury results in impairment of left ventricular (LV) contractile function. There is strong evidence to support the involvement of gut-derived factor(s) transported in mesenteric lymph in the development of burn-related contractile dysfunction; i.e., mesenteric lymph duct ligation (LDL) prevents burn-related contractile depression. However, the cellular mechanisms for altered myocardial contractility of postburn hearts are largely unknown, and the cellular basis for the salutary effects of LDL on cardiac function have not been investigated. We examined contractility, Ca(2+) transients, and L-type Ca(2+) currents (I(Ca)) in LV myocytes isolated from four groups of rats: 1) sham burn, 2) sham burn with LDL (sham + LDL), 3) burn ( approximately 40% of total body surface area burn), and 4) burn with LDL (burn + LDL). Myocytes isolated from hearts at 24 h postburn had a depressed contractility ( approximately 20%) at baseline and blunted responsiveness to elevation of bath Ca(2+). Myocyte contractility was comparable in sham + LDL and sham burn hearts. LDL completely prevented burn-related changes in myocyte contractility. Mechanistically, the decrease in contractility in myocytes from postburn hearts occurred with a decrease in the amplitude of Ca(2+) transients ( approximately 20%) without changes in resting Ca(2+) or Ca(2+) content of the sarcoplasmic reticulum. On the other hand, I(Ca) density was decreased ( approximately 30%) in myocytes from postburn hearts, with unaltered voltage-dependent properties. Thus burn-related myocardial contractile dysfunction is linked with depressed myocyte contractility associated with a decrease in I(Ca) density. These findings also provide strong evidence that mesenteric lymph is involved in the onset of burn-related cardiomyocyte dysfunction.

Mesenteric lymph duct ligation prevents trauma/hemorrhage shock-induced cardiac contractile dysfunction

“…This notion that gut-derived factors carried in the mesenteric lymph can cause acute myocardial dysfunction is further supported by our studies in a burn model where LDL prevented ex vivo burn-induced myocardial depression and where burn lymph recreated this myocyte depressant state in vitro (20,32). On the basis of our previous burn studies showing that the contractile dysfunction of postburn hearts is linked with a decrease in ventricular myocyte Ca 2ϩ transients caused by a decrease in the Ca 2ϩ entry through L-type Ca 2ϩ channels (20), we examined Ca 2ϩ responsiveness of the T/HS hearts.…”

“…The mechanisms by which these lymphatic borne factors are produced as well as the organs involved in their production seem to involve pancreatic enzymes interacting with the ischemic gut (1,14,28). Furthermore, our recent studies measuring cardiac contractility in isolated hearts and myocytes from rats subjected to burn injury (20,32) have shown that mesenteric lymph generated following burn injury directly causes changes in cardiac contractility, thereby supporting the role of mesenteric lymph as a key factor involved in regulating myocardial contractile dysfunction.…”

Redefining the gut as the motor of critical illness

“…Further, mesenteric lymph collected from mice following trauma-hemorrhagic shock (T/HS) and injected into trauma-sham shock (T/SS) mice induces lung injury and demonstrates the same toxic properties of intestinal lymph seen in T/HS (13). Additionally, ligation of the mesenteric lymph duct in either T/HS or in burn injury prevents injury-induced decreases in cardiac contractility and cardiac output (14–16). Perhaps most importantly, ligation of the mesenteric lymphatic duct improves survival in multiple animal models of critical illness (5;17).…”

Cellular Mechanism Underlying Burn Serum-Generated Bidirectional Regulation of Excitation-Contraction Coupling in Isolated Rat Cardiomyocytes

“…Our most recent study has demonstrated that burn trauma induces leaky sarcoplasmic reticulum (SR), leading to partial depletion of SR Ca 2+ content and the resulting diminished systolic Ca 2+ transient and contractile deficit (5). In contrast to the findings on ventricular myocytes isolated from burn-traumatized heart, Yatani and coworkers (6) demonstrated that mesenteric lymph from rats with thermal injury significantly increased the myocyte contractility and systolic Ca 2+ transient in cardiomyocytes isolated from normal rat heart, despite that all the evidence heretofore supports that burn lymph plays an important role in inducing burn-generated cardiac dysfunction (4,7). The contradictory results obtained from these two classes of experiments arouse 2-fold concerns: first, whether the process of cardiomyocyte isolation and the environment for the isolated cells, which is free of burn-generated detrimental factors, change and/or mask some alterations in excitation-contraction (EC) coupling presented in burn-traumatized cardiomyocytes in vivo; second, how does the burn injuryYrelated humoral environment act on the development of burn-generated cardiac dysfunction, and what are the underlying mechanisms?…”