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in Pulmonary Host Defense in Murine Invasive Aspergillosis1
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
Invasive pulmonary aspergillosis is a common and devastating
complication of immunosuppression, whose incidence has increased
dramatically in tandem with the increase in the number of
immunocompromised patients. Given the role of TNF-
in other
pulmonary infections, we hypothesized that TNF- is an important
proximal signal in murine invasive pulmonary aspergillosis.
Intratracheal challenge with Aspergillus fumigatus
conidia in both neutropenic (cyclophosphamide-treated) and
nonneutropenic BALB/c mice resulted in the time-dependent increase in
lung TNF- levels, which correlated with the histologic development
of a patchy, peribronchial infiltration of mononuclear and
polymorphonuclear cells. Ab-mediated neutralization of TNF- resulted
in an increase in mortality in both normal and cyclophosphamide-treated
animals, which was associated with increased lung fungal burden as
determined by histology and as quantified by chitin content. Depletion
of TNF- resulted in a reduced lung neutrophil influx in both normal
and cyclophosphamide-treated animals, which occurred in association
with a decrease in lung levels of the C-X-C chemokine, macrophage
inflammatory protein-2 and the C-C chemokines macrophage inflammatory
protein-1 and JE. In cyclophosphamide-treated animals, intratracheal
administration of a TNF- agonist peptide (TNF70–80) 3
days before, but not concomitant with, the administration of
Aspergillus conidia resulted in improved survival from
9% in control mice to 55% in TNF70–80-treated animals.
These studies indicate that TNF- is a critical component of innate
immunity in both immunocompromised and immunocompetent hosts, and that
pretreatment with a TNF- agonist peptide in a compartmentalized
fashion can significantly enhance resistance to A.
fumigatus in neutropenic animals.
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S. D. Stephens-Romero, A. J. Mednick, and M. Feldmesser The Pathogenesis of Fatal Outcome in Murine Pulmonary Aspergillosis Depends on the Neutrophil Depletion Strategy Infect. Immun., January 1, 2005; 73(1): 114 - 125. [Abstract] [Full Text] [PDF]
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V. Balloy, M. Huerre, J.-P. Latge, and M. Chignard Differences in Patterns of Infection and Inflammation for Corticosteroid Treatment and Chemotherapy in Experimental Invasive Pulmonary Aspergillosis Infect. Immun., January 1, 2005; 73(1): 494 - 503. [Abstract] [Full Text] [PDF]
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 C. M. Hogaboam, K. Takahashi, R. A. B. Ezekowitz, S. L. Kunkel, and J. M. Schuh Mannose-binding lectin deficiency alters the development of fungal asthma: effects on airway response, inflammation, and cytokine profile J. Leukoc. Biol., May 1, 2004; 75(5): 805 - 814. [Abstract] [Full Text] [PDF]
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M. J. Becker, S. de Marie, M. H. A. M. Fens, H. A. Verbrugh, and I. A. J. M. Bakker-Woudenberg Effect of amphotericin B treatment on kinetics of cytokines and parameters of fungal load in neutropenic rats with invasive pulmonary aspergillosis J. Antimicrob. Chemother., September 1, 2003; 52(3): 428 - 434. [Abstract] [Full Text] [PDF]
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H. L. Van Epps, M. Feldmesser, and E. G. Pamer Voriconazole Inhibits Fungal Growth without Impairing Antigen Presentation or T-Cell Activation Antimicrob. Agents Chemother., June 1, 2003; 47(6): 1818 - 1823. [Abstract] [Full Text] [PDF]
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 G. D. Brown, J. Herre, D. L. Williams, J. A. Willment, A. S. J. Marshall, and S. Gordon Dectin-1 Mediates the Biological Effects of {beta}-Glucans J. Exp. Med., May 5, 2003; 197(9): 1119 - 1124. [Abstract] [Full Text] [PDF]
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H. Hebart, C. Bollinger, P. Fisch, J. Sarfati, C. Meisner, M. Baur, J. Loeffler, M. Monod, J.-P. Latge, and H. Einsele Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies Blood, December 15, 2002; 100(13): 4521 - 4528. [Abstract] [Full Text] [PDF]
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B. Mehrad, M. Wiekowski, B. E. Morrison, S.-C. Chen, E. C. Coronel, D. J. Manfra, and S. A. Lira Transient Lung-Specific Expression of the Chemokine KC Improves Outcome in Invasive Aspergillosis Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1263 - 1268. [Abstract] [Full Text] [PDF]
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 S. S. Mambula, K. Sau, P. Henneke, D. T. Golenbock, and S. M. Levitz Toll-like Receptor (TLR) Signaling in Response to Aspergillus fumigatus J. Biol. Chem., October 11, 2002; 277(42): 39320 - 39326. [Abstract] [Full Text] [PDF]
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A. C. Herring, J. Lee, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection Infect. Immun., June 1, 2002; 70(6): 2959 - 2964. [Abstract] [Full Text] [PDF]
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 A. Warris, A. Bjorneklett, P. Gaustad, G. F. Keenan, T. F. Schaible, and J. A. Boscia Invasive Pulmonary Aspergillosis Associated with Infliximab Therapy N. Engl. J. Med., April 5, 2001; 344(14): 1099 - 1100. [Full Text] [PDF]
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J. K. Brieland, C. Jackson, F. Menzel, D. Loebenberg, A. Cacciapuoti, J. Halpern, S. Hurst, T. Muchamuel, R. Debets, R. Kastelein, et al. Cytokine Networking in Lungs of Immunocompetent Mice in Response to Inhaled Aspergillus fumigatus Infect. Immun., March 1, 2001; 69(3): 1554 - 1560. [Abstract] [Full Text] [PDF]
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B. Finkel-Jimenez, M. Wuthrich, T. Brandhorst, and B. S. Klein The WI-1 Adhesin Blocks Phagocyte TNF-{{alpha}} Production, Imparting Pathogenicity on Blastomyces dermatitidis J. Immunol., February 15, 2001; 166(4): 2665 - 2673. [Abstract] [Full Text] [PDF]
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K. Blease, B. Mehrad, N. W. Lukacs, S. L. Kunkel, T. J. Standiford, and C. M. Hogaboam Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure to Asperigillus fumigatus Conidia J. Immunol., February 1, 2001; 166(3): 1832 - 1842. [Abstract] [Full Text] [PDF]
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 F. Reichenberger, J.M. Habicht, A. Gratwohl, and M. Tamm Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients Eur. Respir. J., January 1, 2001; 19(4): 743 - 755. [Abstract] [Full Text] [PDF]
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H. Briscoe, D. R. Roach, N. Meadows, D. Rathjen, and W. J. Britton A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in CD4+ T cell-depleted mice J. Leukoc. Biol., October 1, 2000; 68(4): 538 - 544. [Abstract] [Full Text]
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K. Blease, B. Mehrad, T. J. Standiford, N. W. Lukacs, J. Gosling, L. Boring, I. F. Charo, S. L. Kunkel, and C. M. Hogaboam Enhanced Pulmonary Allergic Responses to Aspergillus in CCR2-/- Mice J. Immunol., September 1, 2000; 165(5): 2603 - 2611. [Abstract] [Full Text] [PDF]
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K. Blease, B. Mehrad, T. J. Standiford, N. W. Lukacs, S. L. Kunkel, S. W. Chensue, B. Lu, C. J. Gerard, and C. M. Hogaboam Airway Remodeling Is Absent in CCR1-/- Mice During Chronic Fungal Allergic Airway Disease J. Immunol., August 1, 2000; 165(3): 1564 - 1572. [Abstract] [Full Text] [PDF]
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B. Mehrad, T. A. Moore, and T. J. Standiford Macrophage Inflammatory Protein-1{alpha} Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts J. Immunol., July 15, 2000; 165(2): 962 - 968. [Abstract] [Full Text] [PDF]
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E. Cenci, A. Mencacci, A. Bacci, F. Bistoni, V. P. Kurup, and L. Romani T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis J. Immunol., July 1, 2000; 165(1): 381 - 388. [Abstract] [Full Text] [PDF]
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C. M. Hogaboam, K. Blease, B. Mehrad, M. L. Steinhauser, T. J. Standiford, S. L. Kunkel, and N. W. Lukacs Chronic Airway Hyperreactivity, Goblet Cell Hyperplasia, and Peribronchial Fibrosis during Allergic Airway Disease Induced by Aspergillus fumigatus Am. J. Pathol., February 1, 2000; 156(2): 723 - 732. [Abstract] [Full Text] [PDF]
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B. Mehrad, R. M. Strieter, T. A. Moore, W. C. Tsai, S. A. Lira, and T. J. Standiford CXC Chemokine Receptor-2 Ligands Are Necessary Components of Neutrophil-Mediated Host Defense in Invasive Pulmonary Aspergillosis J. Immunol., December 1, 1999; 163(11): 6086 - 6094. [Abstract] [Full Text] [PDF]
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