Acute gram-negative bacterial infections are a leading cause of mortality among the nosocomial infections. Increasing numbers of immunosuppressed individuals and growing numbers of antibiotic resistant strains make antibiotic treatment difficult. Neutrophils are the first cells recruited to the site of infection and are critical players in the host defense against gram-negative bacterial pneumonia. Therefore, identification of targets that boost neutrophil-associated host defense in the lung is essential in designing better therapies to control pulmonary infections. Production of chemokines is an important step for neutrophil recruitment. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is important for monocyte and T-lymphocyte influx. It is important for the host defense during Listeria monocytogenes and Streptococcus pneumoniae infection. However, the role of MCP-1 during pulmonary gram-negative infections is not known. We hypothesized that MCP-1 is essential for the host defense during a gram-negative infection. To test the hypothesis, we infected MCP-1 gene-deficient (MCP-1-/-) mice and controls intratracheally (i.t.) with E. coli (106 CFUs/mouse) and Klebsiella pneumoniae (103 CFUs/mouse). We found that MCP-1 is critical for host defense against gram-negative infections, mainly by recruiting neutrophils to the site of infection. MCP-1 utilizes its receptor, CCR2, to recruit neutrophils directly and indirectly by regulating the expression of cytokines (IL-6, TNF-a) and chemokines (KC, MIP-2) through activation of NF-kB and MAPKs. We also observed that MCP-1 can regulate expression of G-CSF and thereby neutrophil numbers in circulation during Kp infection. In addition, exogenous administration of rG-CSF can restore the defects in host defense in MCP-1-/- mice following gram-negative Kp infection. This study demonstrates an unrecognized role of MCP-1 in host defense during gram negative bacterial pneumonia. These findings bolster pleiotropic effects of MCP-1 in the host defense and demonstrate a potential role as a therapeutic agent to augment host defense during acute bacterial pneumonia.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-04182012-091506 |
| Date | 27 April 2012 |
| Creators | Balamayooran, Gayathriy |
| Contributors | Wang, Guoshun, Carstens, Bryan, Penn, Arthur, Chowdury, Shafiqul, Guerrero-Plata, Antonieta, Jeyaseelan, Samithamby |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-04182012-091506/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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