Patients with AIDS continue to die predominantly as a result of respiratory infections. Bacterial empyema with pyogenic organisms is a common complication of pneumonia in patients with AIDS. Though multiple organisms can cause pleural infections in patients with AIDS, one of the commonest organisms to cause empyema is Staphylococcus aureus. It is the hypothesis of this proposal that recruited neutrophils represent important phagocytic cells involved in effective pleural antibacterial host defense in bacterial empyema. We have developed a model of bacterial empyema in CD4 knockout mice that mimics bacterial empyema in patients with AIDS. Pleural mesothelial cells play a critical role in neutrophil recruitment by the production of neutrophil activating and chemotactic chemokines MIP-2, and KC in our murine model of staphylococcal empyema CD4 depletion alters pleural neutrophil recruitment and bacterial clearance by inhibition the in vivo compartmentalized production of the chemokines. Macrophage inflammatory protein-2 (MIP-2) and KC (murine gro-alpha). The inhibitory effect of CD4 depletion is in part due to the relative imbalance between Th1 type Interferon Gamma (IFN-gamma) and Th2 type cytokines, Interleukin-10 (IL-10). We will evaluate our hypothesis both in vivo and in vitro. Using an in vivo model of staphylococcal empyema in CD4, knockout mice, we will evaluate the regulation of MIP-2 and KC by 1TH and 2TH cytokines. In vitro, mesothelial cell responses to S. Aureus by release of neutrophil chemokines and their regulation will be studied. Understanding the mechanism of regulation of neutrophil recruitment to the pleural space may help us discern the pathophysiology of the fulminant bacterial empyema seen in patients with AIDS and may help develop therapeutic modalities that augment host defense responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045338-02
Application #
6170338
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (04))
Program Officer
Laughon, Barbara E
Project Start
1999-07-15
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$169,166
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Nasreen, Najmunnisa; Mohammed, Kamal A; Lai, Yimu et al. (2007) Receptor EphA2 activation with ephrinA1 suppresses growth of malignant mesothelioma (MM). Cancer Lett 258:215-22
Mohammed, Kamal A; Nasreen, Najmunnisa; Tepper, Robert S et al. (2007) Cyclic stretch induces PlGF expression in bronchial airway epithelial cells via nitric oxide release. Am J Physiol Lung Cell Mol Physiol 292:L559-66
Ramirez-Icaza, Gail; Mohammed, Kamal A; Nasreen, Najmunnisa et al. (2004) Th2 cytokines IL-4 and IL-13 downregulate paxillin expression in bronchial airway epithelial cells. J Clin Immunol 24:426-34
Antony, Veena B; Nasreen, Najmunnisa; Mohammed, Kamal A et al. (2004) Talc pleurodesis: basic fibroblast growth factor mediates pleural fibrosis. Chest 126:1522-8
Kilani, Muna M; Mohammed, Kamal A; Nasreen, Najmunnisa et al. (2004) Respiratory syncytial virus causes increased bronchial epithelial permeability. Chest 126:186-91
Nasreen, Najmunnisa; Mohammed, Kamal A; Sanders, Kerry et al. (2003) Pleural mesothelial cell (PMC) defense mechanisms against malignancy. Oncol Res 14:155-61
Sharma, Ramit K; Mohammed, Kamal A; Nasreen, Najmunnisa et al. (2003) Defensive role of pleural mesothelial cell sialomucins in tumor metastasis. Chest 124:682-7
Sriram, P S; Mohammed, Kamal A; Nasreen, Najmunnisa et al. (2002) Adherence of ovarian cancer cells induces pleural mesothelial cell (PMC) permeability. Oncol Res 13:79-85
Nasreen, Najmunnisa; Mohammed, Kamal A; Hardwick, Joyce et al. (2002) Low molecular weight hyaluronan induces malignant mesothelioma cell (MMC) proliferation and haptotaxis: role of CD44 receptor in MMC proliferation and haptotaxis. Oncol Res 13:71-8
Lundien, Matthew C; Mohammed, Kamal A; Nasreen, Najmunnisa et al. (2002) Induction of MCP-1 expression in airway epithelial cells: role of CCR2 receptor in airway epithelial injury. J Clin Immunol 22:144-52

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