title: Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis.
abstract: 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-alpha in other pulmonary infections, we hypothesized that TNF-alpha 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-alpha levels, which correlated with the histologic development of a patchy, peribronchial infiltration of mononuclear and polymorphonuclear cells. Ab-mediated neutralization of TNF-alpha 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-alpha 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-1alpha and JE. In cyclophosphamide-treated animals, intratracheal administration of a TNF-alpha 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-alpha is a critical component of innate immunity in both immunocompromised and immunocompetent hosts, and that pretreatment with a TNF-alpha agonist peptide in a compartmentalized fashion can significantly enhance resistance to A. fumigatus in neutropenic animals.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mehrad
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001228:Aspergillosis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001232:Aspergillus fumigatus; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009503:Neutropenia / Q000150:complications / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism