Abstract
BackgroundThe balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues. Excessive ROS states occur in diseases such as ARDS and Idiopathic Pulmonary Fibrosis. Redox imbalance breaks down the extracellular matrix component hyaluronan (HA) into fragments that activate innate immune responses and perpetuate tissue injury. HA fragments, via a TLR and NF-κB pathway, induce inflammatory gene expression in macrophages and epithelial cells. NAC and DMSO are potent anti-oxidants which may help balance excess ROS states.MethodsWe evaluated the effect of H2O2, NAC and DMSO on HA fragment induced inflammatory gene expression in alveolar macrophages and epithelial cells.ResultsNAC and DMSO inhibit HA fragment-induced expression of TNF-α and KC protein in alveolar and peritoneal macrophages. NAC and DMSO also show a dose dependent inhibition of IP-10 protein expression, but not IL-8 protein, in alveolar epithelial cells. In addition, H2O2 synergizes with HA fragments to induce inflammatory genes, which are inhibited by NAC. Mechanistically, NAC and DMSO inhibit HA induced gene expression by inhibiting NF-κB activation, but NAC had no influence on HA-fragment-AP-1 mediated gene expression.ConclusionROS play a central role in a pathophysiologic "vicious cycle" of inflammation: tissue injury generates ROS, which fragment the extracellular matrix HA, which in turn synergize with ROS to activate the innate immune system and further promote ROS, HA fragment generation, inflammation, tissue injury and ultimately fibrosis. The anti-oxidants NAC and DMSO, by inhibiting the HA induced inflammatory gene expression, may help re-balance excessive ROS induced inflammation.
Highlights
The balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues
To demonstrate that the ability of dimethyl sulfoxide (DMSO) to inhibit HA-fragment induced cytokine expression was not idiosyncratic to the MH-S alveolar macrophage cell line, we examined its effect on HA fragment-stimulated genes in primary macrophages
Thioglycollate elicited peritoneal macrophages (PEC) from C3H/Hej LPS hyporesponsive mice were stimulated with HA fragments in the presence of different concentrations of DMSO for 18 h and TNF-α was measured in cell supernatants
Summary
The balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues. Excessive ROS states occur in diseases such as ARDS and Idiopathic Pulmonary Fibrosis. NAC and DMSO are potent anti-oxidants which may help balance excess ROS states. In normal physiological conditions a homeostatic balance exists between the formation of reactive oxygen species (ROS) and their removal by endogenous antioxidant scavenging compounds [1]. ROS are involved in signal transduction and gene activation, and can contribute to host cell and organ damage [2]. When cellular production of ROS overwhelms its antioxidant capacity, a state of oxidative stress is reached leading to serious cellular injuries and contributing to the pathogenesis of several diseases like ARDS, Asthma, COPD, cancer and Idiopathic Pulmonary Fibrosis [3]. Recent reports suggest that counteracting this state of oxidative stress with the anti-oxidant N-acetylcysteine slows down the progression of this deadly disease [6]
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