Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of the skin and remote organs

doi:10.1016/j.burns.2005.01.012

Burns

Volume 31, Issue 5, August 2005, Pages 587-596

https://doi.org/10.1016/j.burns.2005.01.012 Get rights and content

Abstract

Thermal injury elicits several systemic consequences, among them the systemic inflammatory response where the generation of reactive oxygen radicals and lipid peroxidation play important roles. In the present study, we investigated whether the leukotriene receptor blocker montelukast is protective against burn-induced remote organ injury. Under brief ether anaesthesia, shaved dorsum of the rats was exposed to 90 °C (burn group) or 25 °C (control group) water bath for 10 s. Montelukast (10 mg/kg) or saline was administered intraperitoneally immediately after and at the 12th hour of the burn injury. Rats were decapitated 24 h after burn injury and the tissue samples from lung, liver, kidney and skin were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and creatinine, urea (BUN) concentrations were determined to assess liver and kidney function, respectively. Tumor necrosis factor-α (TNF-α) and lactate dehydrogenase (LDH) were also assayed in serum samples. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, serum ALT, AST and BUN levels, as well as LDH and TNF-α, were elevated in the burn group as compared to control group. On the other hand, montelukast treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by thermal trauma. Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on burn-induced damage in remote organs and protects against oxidative organ damage by a neutrophil-dependent mechanism.

Introduction

Thermal trauma, one of the most common problems faced in the emergency room, may cause damage to multiple organs distant from the original burn wound and may lead to multiorgan failure. Burn trauma produces significant fluid shifts that, in turn, reduce cardiac output and tissue perfusion and thus causes ischemia of the tissues [1]. While aggressive postburn volume replacement increases oxygen delivery to previously ischemic tissue, this restoration of oxygen delivery is thought to initiate a series of deleterious events that exacerbate tissue injury that occurred during low flow state [2].

The inflammatory response to burn is extremely complex, resulting in local tissue damage and deleterious systemic effects in all the organ systems distant from the original wound. Several studies have demonstrated that burn injury is associated with lipid peroxidation, which is an autocatalytic mechanism leading to oxidative destruction of cellular membranes, and their destruction can lead to the production of toxic, reactive metabolites and cell death [3], [4]. A growing body of evidence suggests that the activation of a proinflammatory cascade after major burn is responsible for the development of immune dysfunction, and susceptibility to sepsis and multiple organ failure [1]. In addition to the well-documented role of neutrophils and endothelial cells in oxidative tissue damage or organ failure [5], [6], macrophages are also major producers of pro-inflammatory mediators, and their productive capacity for these mediators, such as prostaglandin E2, reactive nitrogen intermediates, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, is markedly enhanced following thermal injury [7], [8]. There have been several reports indicating that circulating levels of IL-1β, IL-6 and TNF-α are increased in patients with burn injury [9].

Leukotrienes, the products generated by the 5-lipoxygenase pathway, are particularly important in inflammation; indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents [10]. There are a number of studies demonstrating the role of leukotrienes as mediators of the gastric damage induced by ethanol or other noxious substances [11], [12]. Cysteinyl leukotrienes, namely leukotrienes C₄, D₄ and E₄ (LTC₄, LTD₄ and LTE₄) are secreted mainly by eosinophils, mast cells, monocytes and macrophages, and they exert a variety of actions which emphasize their importance as pathogenic elements in inflammatory states [13], [14]. A selective reversible cys-leukotriene-1 receptor (LTD₄ receptor) antagonist, montelukast (MK-0476), is used in the treatment of asthma and is reported to reduce eosinophilic inflammation in the airways [15], [16], while leukotriene receptor antagonists or biosynthesis inhibitors have been reported to ameliorate ethanol-induced gastric mucosal damage [11], [17], and experimental colitis [18]. Previous studies in burned patients [19] and experimental studies [20] have shown that the lipoxygenase metabolite LTB4 and cysteinyl leukotrienes are involved in the tissue trauma. However, the potential effect of montelukast in thermal injury-induced multiple organ damage was not studied so far.

Based on these findings, in the present study, the putative protective effect of montelukast against burn-induced skin- and remote organ-injury was examined using biochemical and histopathological approaches, while the functional impairments were monitored by hepatic and renal function tests.

Section snippets

Animals

Wistar albino rats of both sexes, weighing 200–250 g, were obtained from Marmara University School of Medicine Animal House. The rats were kept at a constant temperature (22 ± 1 °C) with 12-h light:12-h dark cycles, were fed with standard rat chow and were fasted for 12 h before the experiments, but were allowed free access to water. All experimental protocols were approved by the Marmara University School of Medicine Animal Care and Use Committee.

Thermal injury and experimental design

Under brief ether anesthesia, dorsum of the rats was

Results

Burn-induced increase in the skin wet-weight, as compared to control group (p < 0.001), was abolished in montelukast-treated group (p < 0.01)(Fig. 1A). TNF-α levels were also significantly increased in saline-treated burn group, while this burn-induced rise in serum TNF-α level was significantly reversed with montelukast treatment (Fig. 1B).

BUN and creatinine concentrations were studied to assess renal function, while serum AST and ALT levels were determined to evaluate hepatic function. BUN level

Discussion

As evidenced by alterations in malondialdehyde and glutathione levels, myeloperoxidase activity and collagen content, the results of the present study demonstrate that the burn-induced local damage, as well as distant organ injury in the lung, liver and kidney tissues, is ameliorated by montelukast treatment. Moreover, morphological changes in the injured tissues and impairments in hepatic and renal functions due to burn trauma were also improved by montelukast treatment, which also reduced the

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Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of the skin and remote organs

Abstract

Introduction

Section snippets

Animals

Thermal injury and experimental design

Results

Discussion

Toxicology

J Urol

Burns

Burns

Gastroenterology

Gastroenterology

Biocehm Biophys Res Commun

Eur J Pharmacol

Burns Incl Therm Inj

Clin Chem Acta

J Invest Dermatol

Burns Incl Therm Inj

Free Radic Biol Med

Prostaglandins Leukot Essent Fatty Acids

Prostaglandins

Burns

Burns

Burns

Biochim Biophys Acta

Pharmac Ther

Systemic responses to burn injury

Turk J Med Sci

Systemic lipid peroxidation and inflammation induced by thermal injury persists into the post resuscitation period

J Trauma

Pathophysiologic events related to thermal injury of skin

J Trauma

The role of mediators in the response to thermal injury

World J Surg

Nitric oxide and macrophage function

Annu Rev Immunol