Acute lung injury (ALI) is characterized by pulmonary cellular infiltration and edema resulting from endothelial cell (EndoC) and epithelial cell (EpiC) injury, the mechanism of which remains unclear. ALI can also lead to acute respiratory distress syndrome (ARDS), which is often lethal. It occurs in several disorders affecting ~150,000 patients per year in US with a mortality rate of ~50%. One of the common features of ALI is the inflammation in the lungs and the production of cytokines. In the current investigation, we will use a mouse model of superantigen such as staphylococcal enterotoxin-induced ALI to delineate the immunopathogenesis mechanisms involved. Staphylococcal enterotoxins and other related exotoxins have been classified by the Center for Disease Control as potential biological warfare agents. It is well established that staphylococcal enterotoxins activate a large percentage of T cells expressing an invariant T cell receptor. Preliminary studies from our lab have demonstrated that staphylococcal enterotoxin B (SEB) treatment of mice led to marked upregulation of CD44 expression on lymphocytes, which migrate to the lungs and cause vascular leak by using CD44 as an effector molecule. We have shown that CD44 knock out (KO) mice are more resistant to SEB-induced pulmonary damage and furthermore, treatment of CD44 wild-type (WT) mice with antibodies against CD44 can effectively block SEB-mediated pulmonary injury. SEB treatment led to induction of IL-2, IFN-gamma and TNF-alpha production and increased NK and NKT cell infiltration in the lungs. Based on this, we will test the central hypothesis that SEB-mediated CD44 expression on cytolytic lymphocytes plays a critical role in lung injury.
The specific aims of the current study are as follows: 1) To examine the role of SEB-reactive T cells, cytotoxic T cells, NK cells and NKT cells in CD44WT and CD44KO mice in induction of vascular leak and ALI. 2) CD44 bone marrow chimeras will be used to address the role of CD44 expression on cytotoxic lymphocytes, pulmonary EndoC and EpiC in SEB-induced ALI. 3) To determine the CD44 isoforms involved in lung injury by using siRNA technology 4) The role of CD44v6 and v7 isoforms in lung injury will be determined by using specific exon knockout mice 5) To develop strategies to prevent or treat lung injury using mimetics of CD44 or its ligand. Understanding the mechanism by which cytolytic lymphocytes cause alveolar EndoC and EpiC injury would help in developing novel strategies which could serve as potential biodefense against acute lung injury caused by bacterial toxins. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI058300-03
Application #
7126665
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Sawyer, Richard T
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2005-08-15
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$226,359
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash S (2018) Evaluation of Cell Proliferation and Apoptosis in Immunotoxicity Testing. Methods Mol Biol 1803:209-230
Guan, Hongbing; Singh, Narendra P; Singh, Udai P et al. (2012) Resveratrol prevents endothelial cells injury in high-dose interleukin-2 therapy against melanoma. PLoS One 7:e35650
Ariza, Maria Eugenia; Ramakrishnan, Rupal; Singh, Narendra P et al. (2011) Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-like receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells. J Biol Chem 286:24-34
Zhou, Juhua; Nagarkatti, Prakash S; Zhong, Yin et al. (2011) Implications of single nucleotide polymorphisms in CD44 exon 2 for risk of breast cancer. Eur J Cancer Prev 20:396-402
Guan, Hongbing; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2011) CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune ence J Immunol 186:6955-64
Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Vakharia, Dilip et al. (2010) Evaluation of apoptosis in immunotoxicity testing. Methods Mol Biol 598:241-57
Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin et al. (2010) Immune modulation by chondroitin sulfate and its degraded disaccharide product in the development of an experimental model of multiple sclerosis. J Neuroimmunol 223:55-64
Singh, Udai P; Singh, Narendra P; Singh, Balwan et al. (2010) Resveratrol (trans-3,5,4'-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther 332:829-39
Zhou, Juhua; Nagarkatti, Prakash S; Zhong, Yin et al. (2010) Unique SNP in CD44 intron 1 and its role in breast cancer development. Anticancer Res 30:1263-72
Hegde, Venkatesh L; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2010) Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol 40:3358-71

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