Role of oxidative stress and antioxidant therapy in acute and chronic phases of sulfur mustard injuries: a review

Abstract

Sulfur mustard (SM) is a chemical compound that preferentially targets ocular, cutaneous and pulmonary tissues. Although pathologic effect of SM has been extensively considered, molecular and cellular mechanism of its toxicity, especially at the chronic phase of injury is not well-understood. Excessive production of reactive oxygen species (ROS) and oxidative stress (OS) appears to be involved in SM-induced injuries. SM may trigger several molecular and cellular pathways linked to OS and inflammation that can subsequently result in cell death and apoptosis. At the acute phase of injury, SM can enhance ROS production and OS by reducing the activity of antioxidants, depletion of intercellular glutathione (GSH), decreasing the productivity of GSH-dependent antioxidants, mitochondrial deficiency, accumulation of leukocytes and pro-inflammatory cytokines. Overexpression of ROS producing enzymes and down-regulation of antioxidant enzymes are probably the major events by which SM leads to OS at the chronic phase of injury. Therefore, antioxidant therapy with potent antioxidants such as N-acetylcysteine and curcumin may be helpful to mitigate SM-induced OS damages. This review aims to discuss the proposed cellular and molecular mechanisms of acute and delayed SM toxicity, the importance of OS and mechanisms by which SM increases OS either at the acute or chronic phases of injuries along with research on antioxidant therapy as a suitable antidote.

Impact of melatonin effects on toxicology of vesicant chemical warfare agents: When science meets reality

“…The fact that the Chemical Weapons Convention has not yet achieved universality and the suspicion that some nations have CWA capabilities (33), urges to find novel treatments for post-exposure disorders. In response to this challenge, ROS scavenging, oxidative/nitrosative stress mitigation, antiinflammatory capability, preservation of membrane and intracellular macromolecules, and abrogation of mitochondrial anoikis equip melatonin for counteracting the cytotoxicity of alkylating agents leading to a promising therapy option (34)(35)(36)(37)(38). Accordingly, melatonin has demonstrated biochemical and morphological protection against the respiratory tract, the bladder and the kidney damage induced by mustard vesicant agents (36,(39)(40)(41)(42)(43).…”

“…In this context, the capacity of melatonin to modulate the inflammation-immune axis (48,49) should mitigate the pathological features induced by sulfur mustard through the modulation of the inflammation-immune axis. Some studies have suggested that the enhancement of oxidative species production or weakening of antioxidant mechanisms are crucial in the acute toxicity of sulfur mustard and long-term effects following acute poisoning (22,38,(50)(51)(52)(53). The powerful nitrosating agent peroxynitrite (ONOO • ) is involved in detrimental effects of all mustards as it covalently modifies all the principal types of biomolecules including membrane lipids, thiols, proteins and purine and pyrimidine bases (54)(55)(56).…”

“…The precise molecular details of the cellular pathophysiology triggered by acute sulfur mustard intoxication or by repeated low-dose exposure still wait to be examined (79). Nevertheless, as for other toxics chemical modification of DNA and other macromolecules, inflammation and apoptosis induction, ROS imbalance, depletion of antioxidant defenses and the subsequent emergence of oxidative/nitrosative stress are the most plausible cytotoxic mechanisms postulated (38,80). Conversely, the incapacitating complications and progressive health deterioration after sulfur mustard/nitrogen mustard injury currently lack delineated mechanistic support (81,82).…”

Deciphering the role of microRNAs in mustard gas–induced toxicity

“…23,24,85 It also leads to the generation of reactive oxygen species, causing oxidative damage to cells and mitochondria as well as the depletion of antioxidant enzymes, such as glutathione. 21,[86][87][88][89][90] Here, we will discuss in detail the changes in miR-NAs in the different biological systems upon SM exposure (Table 1).…”

N-Acetylcysteine as a treatment for sulphur mustard poisoning

“…Sulphur mustard is a highly reactive bifunctional alkylating agent, and as such is able to react rapidly with a broad range of cellular constituents and molecular targets. This has resulted in numerous hypotheses being proposed and it has been well recognized as causing the production of reactive nitrogen and oxygen species [ [31] , [32] , [33] , [34] , [35] ], as well as disturbing an array of molecular pathways including; intracellular calcium, anion and pH regulation, poly(ADP-ribose polymerase (PARP) activation, DNA damage and repair, apoptosis induction, inflammation, membrane bound receptors, signalling molecules and extracellular matrices [ 2 , 3 , 11 , 14 , 15 , [36] , [37] , [38] , [39] , [40] , [41] , [42] ]. However, the pathways that ultimately lead to toxicity remain elusive and investigators continue their efforts to define the progression of biochemical/molecular events from exposure to the ultimate expression of overt toxicity.…”