Cysteine/cystine redox state in lung injury and fibrosis
by Iyer, Smita S., Ph.D., EMORY UNIVERSITY, 2008, 234 pages; 3396817

Abstract:

Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are lung diseases with significant morbidity and mortality. Glutathione (GSH) is oxidized in both ALI and IPF, but little is known about the regulation of the precursor cysteine (Cys) pool. The studies described in this dissertation establish that the redox state (Eh) of the Cys/cystine (CySS) couple is a biomarker of oxidative stress in experimental ALI and IPF, and varies independently from the redox state of the GSH/glutathione disulfide (GSSG) couple during inflammation, injury, and fibrosis in the lung.

In the first study, we identified that plasma Eh Cys/CySS is highly oxidized relative to Eh GSH/GSSG during the acute phase of lung injury induced by endotoxin. In vitro, oxidized E h Cys/CySS increased adhesion of leukocytes to the pulmonary endothelium, suggesting that early oxidation of Cys/CySS may potentiate neutrophil influx into the lungs.

To further understand the relationship between Eh Cys/CySS and inflammation, we modified extracellular Eh Cys/CySS and determined levels of the pro-inflammatory cytokine, interleukin (IL)-1β. Results showed that oxidized Eh Cys/CySS increased IL-1β levels in monocytes, and that dietary treatment to protect against plasma Eh Cys/CySS oxidation decreased plasma and lung levels of IL-1β in endotoxin-challenged mice. Analysis of Eh Cys/CySS and IL-1β in human plasma revealed a significant positive association between oxidized Eh Cys/CySS and IL-1β, independent of age, gender, and BMI.

Additionally, we examined plasma Cys and GSH redox states during the resolution of inflammation in response to exogenously infused bone marrow derived mesenchymal stem cells (BMDMSC). Results showed a sequential preservation of systemic Cys and GSH pools in response to BMDMSC infusion.

Because lung injury is an upstream event in fibrosis, we assessed the dynamics of Cys redox state in a model of lung fibrosis. Results showed oxidation of plasma Eh Cys/CySS in the absence of changes to Eh GSH/GSSG. Furthermore, oxidation of Eh Cys/CySS in the lung lining fluid was associated with the induction of pro-fibrotic markers in the lung, suggesting that oxidation of Cys/CySS during lung injury may contribute to fibrosis.

 
AdvisersDean P. Jones; Mauricio Rojas
SchoolEMORY UNIVERSITY
SourceDAI/B 71-03, p. , Apr 2010
Source TypeDissertation
SubjectsNutrition; Pathology; Immunology
Publication Number3396817
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