Pulmonary granulomatous diseases are often highly destructive and extremely difficult to manage, requiring potent anti-inflammatory drugs that can compromise the patient's immunologic and metabolic integrity. In order to elucidate the factors dictating the induction and maintenance of these lesions, this proposal will examine the production/interaction of key chemical signals by peripheral blood monocytes, alveolar macrophages and granuloma macrophages from animals with hypersensitivity and foreign body-type lung granulomas. The sequential production of interleukin-1 (IL-1), fibroblast growth factor, arachidonate metabolites, and tumor necrosis factor (TNF) will be analyzed and related to local inflammatory events and associated systemic changes. In addition to the above monocyte/macrophage-derived mediators, a concomitant assessment of serum for the acute phase protein serum amyloid-P, and cell-free bronchoalveolar lavage fluid, for interleukins, TNF, and arachidonic acid metabolites, will be made. The in vivo relevance of IL-1 and TNF will be addressed by a) depleting IL-1 and TNF with specific antibodies at various times during granuloma development and, b) using IL-1 and TNF coated beads as granuloma-inducing agents. Two established models of pulmonary granulomas will be employed: hypersensitivity-type pulmonary granuloma will be induced by embolization of Schistosoma mansoni eggs resulting in a highly active, T-cell mediated lesion; and foreign body-type granulomas will be induced by the embolization of Sephadex beads. Techniques and methodologies employed throughout this proposal include: lymphocyte and fibroblast proliferative assays, bioassays for TNF, radioimmunoassays, and high pressure liquid chromatography. A unique aspect of this proposal is the implementation of these models to evaluate approaches to therapeutic management of pulmonary granulomatous diseases. The therapeutic usefulness of specific protocols will be assessed by examining morphologic/morphometric alterations at the local lesion level as well as molecular mediator changes at the cellular level. This study will provide important knowledge regarding 1) the role of monocyte/macrophage mediators in granuloma development, 2) parameters which reflect active granulomatous inflammation and 3) the mechanism and efficacy of pharmacologic manipulation of granuloma formation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035276-04
Application #
3349029
Study Section
Pathology A Study Section (PTHA)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Trujillo, Glenda; O'Connor, Erica C; Kunkel, Steven L et al. (2008) A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin-induced pulmonary fibrosis. Am J Pathol 172:1209-21
Wen, Haitao; Hogaboam, Cory M; Gauldie, Jack et al. (2006) Severe sepsis exacerbates cell-mediated immunity in the lung due to an altered dendritic cell cytokine profile. Am J Pathol 168:1940-50
Freeman, Christine M; Stolberg, Valerie R; Chiu, Bo-Chin et al. (2006) CCR4 participation in Th type 1 (mycobacterial) and Th type 2 (schistosomal) anamnestic pulmonary granulomatous responses. J Immunol 177:4149-58
Ness, Traci L; Ewing, Jillian L; Hogaboam, Cory M et al. (2006) CCR4 is a key modulator of innate immune responses. J Immunol 177:7531-9
Cheng, Sara S; Lukacs, Nicholas W; Kunkel, Steven L (2002) Eotaxin/CCL11 is a negative regulator of neutrophil recruitment in a murine model of endotoxemia. Exp Mol Pathol 73:1-8
Blease, Kate; Schuh, Jane M; Jakubzick, Claudia et al. (2002) Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am J Pathol 160:481-90
Cheng, Sara S; Lukacs, Nicholas W; Kunkel, Steven L (2002) Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells. J Immunol 168:2887-94
Cheng, S S; Lai, J J; Lukacs, N W et al. (2001) Granulocyte-macrophage colony stimulating factor up-regulates CCR1 in human neutrophils. J Immunol 166:1178-84
Blease, K; Jakubzick, C; Westwick, J et al. (2001) Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J Immunol 166:5219-24
Lukacs, N W; Hogaboam, C; Chensue, S W et al. (2001) Type 1/type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 120:5S-8S

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