The pathogenesis of fibrosis that develops in idiopathic pulmonary fibrosis and the airways of asthmatics remains to be delineated, and effective treatments for these progressive fibrotic processes are needed. Eosinophils are important cellular participants in the pathogenesis of parenchymal and airway pulmonary fibrosis. Eosinophils are potential sources of several profibrotic cytokines, including connective tissue growth factor (CTGF), transforming growth factor (TGF)beta1, TGFalpha, interleukin (IL)-4, and IL-13; and within pulmonary fibrotic tissues, eosinophils are documented sources of fibrogenic cytokines, including CTGF and TGFbeta1. In murine models of pulmonaryfibrosis, experimental modalities that block eosinophil recruitment and activation have led to decreased fibrosis. Thus, eosinophils contribute centrally to the pathogenesis of pulmonary fibrosis. As participants in pulmonary fibrosis, human eosinophils have several distinct and unique functional capabilities. Notably, eosinophils contain already preformed stores of profibrotic cytokines that are rapidly releasable from cytoplasmic granules by means of vesicular transport. The highly regulated, but largely undefined, mechanisms that govern the secretion of preformed profibrotic cytokines for their extracellular release or plasma membrane expression by eosinophils are central to the understanding and control of eosinophil involvement in pulmonary fibrogenesis. Eosinophils by juxtacrine and paracrine mechanisms can modulate the functioning of adjacent fibroblasts and other cells in these lesions; and conversely, fibroblasts and other cells are sources of stimuli that can modulate eosinophil functioning. The central hypothesis is that eosinophils, by means of their cell-cell interactions and their regulated secretion and expression of fibrogenic cytokines, have major roles in the pathogenesis of parenchymal and airway pulmonary fibrosis.
The aims are to delineate the underlying mechanisms that regulate eosinophil secretion and expression of preformed profibrotic cytokines and to investigate functional interactions between eosinophils and lung fibroblasts. Determining the mechanisms that govern eosinophil-fibroblast interactions will help to understand the development of parenchymal or airway fibrosis and may identify steps amenable to therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL070270-01
Application #
6465037
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
2002-03-31
Project End
2006-02-28
Budget Start
2002-03-31
Budget End
2003-02-28
Support Year
1
Fiscal Year
2002
Total Cost
$382,500
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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Wan, Hsiao-Ching; Melo, Rossana C N; Jin, Zhoung et al. (2007) Roles and origins of leukocyte lipid bodies: proteomic and ultrastructural studies. FASEB J 21:167-78
Spencer, Lisa A; Melo, Rossana C N; Perez, Sandra A C et al. (2006) Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion. Proc Natl Acad Sci U S A 103:3333-8
Melo, Rossana C N; Weller, Peter F; Dvorak, Ann M (2005) Activated human eosinophils. Int Arch Allergy Immunol 138:347-9
Melo, Rossana C N; Spencer, Lisa A; Perez, Sandra A C et al. (2005) Human eosinophils secrete preformed, granule-stored interleukin-4 through distinct vesicular compartments. Traffic 6:1047-57

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