The Acquired Immunodeficiency Syndrome (AIDS) is an urgent world-wide clinical problem. Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and mortality in these patients. Inhaled pentamidine isethionate has been used both for treatment of and prophylaxis against Pneumocystis carinii pneumonia. However, the mechanism of action of pentamidine isethionate against Pneumocystis carinii remains unknown. Pulmonary alveolar macrophages are the primary resident host defense cell in the lung and are capable of releasing toxic oxygen radicals which can injure Pneumocystis carinii. We hypothesize that Pentamidine isethionate activates alveolar macrophages via signal transduction pathways initiated by increases in intracellular [Ca2+]i which activates the oxidase enzyme leading to the release of potent oxygen radicals such as superoxide anion (O2-) nitric oxide (NO) and peroxynitrite anion (ONOO) in vivo and in vitro. These activated macrophages also release IL-8 and TNF-a potent proinflammatory cytokines which have both direct and indirect actions on P. carinii. Inhaled pentamidine as prophylactic treatment against Pneumocystis carinii pneumonia is an attempt to target drug therapy in an organ specific, non-toxic manner. The development of a rat model that closely mimics the human situation allows us to evaluate the mechanism of action of pentamidine and define its effects on lung cells both in the short and long term. Determination of the mechanism of action of inhaled pentamidine may improve clinical management of immunosuppressed patients with Pneumocystis carinii pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044281-04A1
Application #
3363024
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1990-04-01
Project End
1996-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Mohammed, K A; Nasreen, N; Ward, M J et al. (1998) Macrophage inflammatory protein-1alpha C-C chemokine in parapneumonic pleural effusions. J Lab Clin Med 132:202-9
Kunkel, S L (1996) Th1- and Th2-type cytokines regulate chemokine expression. Biol Signals 5:197-202
Antony, V B; Hott, J W; Kunkel, S L et al. (1995) Pleural mesothelial cell expression of C-C (monocyte chemotactic peptide) and C-X-C (interleukin 8) chemokines. Am J Respir Cell Mol Biol 12:581-8
Kunkel, S L; Lukacs, N; Strieter, R M (1995) Chemokines and their role in human disease. Agents Actions Suppl 46:11-22
Kasama, T; Strieter, R M; Lukacs, N W et al. (1995) Interferon gamma modulates the expression of neutrophil-derived chemokines. J Investig Med 43:58-67
Pottratz, S T; Paulsrud, J R; Smith, J S et al. (1994) Evidence for Pneumocystis carinii binding to a cell-free substrate: role of the adhesive protein fibronectin. J Lab Clin Med 123:273-81
Hott, J W; Godbey, S W; Antony, V B (1994) Mesothelial cell modulation of pleural repair: thrombin stimulated mesothelial cells release prostaglandin E2. Prostaglandins Leukot Essent Fatty Acids 51:329-35
Antony, V B; Godbey, S W; Kunkel, S L et al. (1993) Recruitment of inflammatory cells to the pleural space. Chemotactic cytokines, IL-8, and monocyte chemotactic peptide-1 in human pleural fluids. J Immunol 151:7216-23
Hott, J W; Sparks, J A; Godbey, S W et al. (1992) Mesothelial cell response to pleural injury: thrombin-induced proliferation and chemotaxis of rat pleural mesothelial cells. Am J Respir Cell Mol Biol 6:421-5
Antony, V B; Rothfuss, K J; Godbey, S W et al. (1992) Mechanism of tetracycline-hydrochloride-induced pleurodesis. Tetracycline-hydrochloride-stimulated mesothelial cells produce a growth-factor-like activity for fibroblasts. Am Rev Respir Dis 146:1009-13

Showing the most recent 10 out of 11 publications