Overview

Antioxidant Protein Peroxiredoxin V
Tobacco cigarette smoke is the most common environmental factor directly inducing oxidative stress. Exposure to cigarette smoke also leads to airway inflammation. Oxidative and cytotoxic impact of smoke on the bronchial epithelium is further exacerbated by endogenous Reactive Oxygen Species (ROS), released by inflammatory cells. To assure protection of airways, several antioxidant systems are present in the epithelial cells.

Functionally important antioxidant proteins – peroxiredoxins (PRX I-VI) are among multiple antioxidant systems in the epithelium of airways. PRXs are able to neutralize the activity of ROS by electron transfer from thioredoxins or cyclophilins. The role and regulation of Peroxiredoxin V (PRXV) in the airway pathology have not been studied. Our goal is to evaluate the significance, function, regulation, and protective role of Peroxiredoxin V in airway epithelium in defense against oxidative damage induced by tobacco smoke.

This long-term investigation of PRXV provides an important observation that PRXV is one of the major enzymes of cell antioxidant defense. Down-regulation of PRXV results in significant increase in cell susceptibility to oxidative stress and apoptosis, even despite existence of redundant antioxidant system in the cells.

This finding emphasizes the outstanding role, which PRXV is likely to play in antioxidant defense, possibly due to its unique ability for nuclear translocation and antioxidant protection of DNA. According to our results cigarette smoke significantly reduce mRNA levels for PRXV and expression of PRXV in the epithelium of airways.

Stem and progenitor cell-based therapy is emerging as a new concept for the treatment of various diseases.  The concept of stem cell therapy for lung fibro-proliferative diseases is to regenerate normal lung epithelial structure by transplantation of exogenous or recruitment of endogenous stem/progenitor cells. It is unknown whether circulating stem cells significantly contribute to the lung remodeling following bacterial inflammatory injuries. Engraftment of stem cells occurs only following severe injury. Transformation of engrafted pluripotent mesenchimal stem cell into the epithelial cell is the key element of the concept.  How to direct the differentiation of mesenchimal stem cells (MSC) into the epithelial cells, but not fibroblasts, in an inflammatory environment? Mechanisms, which direct such a differentiation decision of stem cells, remain largely unknown.

Our long-term goal is to elaborate on stem-cell based therapy for acute and chronic lung diseases. We have shown that bone marrow-derived stem cells graft to the lung and transform into epithelial, endothelial cells and fibroblasts, following bacterial pneumonia. The family of Mitogen-Activated Protein Kinases (MAPK) is a key player in inflammatory reactions and cell differentiation.

MAPK is activated during inflammation in the lung and in lung-engrafted stem cells, and is likely to determine differentiation of lung-engrafted mesenchimal stem cells (MSC). Our hypothesis is that circulating MSCs significantly contribute to post-inflammatory lung remodeling. Persistent activation of the MAPK family in lung inflammation prevents differentiation of MSC into the epithelial cells, and favors fibroblast differentiation. MAPK blockade may enhance differentiation of stem cells into the epithelial cells.

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Toll Receptor Blockade
The long term goal of this study is to develop small-molecule based method for prevention of septic shock and death by blockade of endotoxin receptors Toll4 and CD14 in hyperimmune phase of sepsis. This small-molecule-based therapy will allow a new highly economical way to improve survival in patients with systemic inflammation or high risk of it.

We have demonstrated, that intravenous administration of polyoxyethylated alkylphenol compound Tyloxapol prevents from acute reactions (febrile, hemodynamic, release of inflammatory mediators and cytokines) to endotoxin of E.coli by blockade of endotoxin receptor cluster. Based on these findings, our hypothesis is that Tyloxapol may effectively inhibit hyper activation of the immune cells by lipopolysaccharides of Salmonella bacteria via partial blockade of receptors of innate immunity (Toll4-CD14). Transcriptional or translational blockade of Toll4-CD14 can be used in combination with antibiotics for the prevention or treatment of septic shock and systemic inflammation in Salmonella-induced sepsis.