Abstract

and specific aims): Neutrophil elastase is a potent proteolytic enzyme believed to be important in the host defense and inflammatory functions of the polymorphonuclear leukocyte (PMN). Abnormal expression of this proteinase may lead to a variety of destructive diseases including pulmonary emphysema. The role of human neutrophil elastase (HNE) in the pathogenesis of the usual form of emphysema associated with cigarette smoking is unclear. In fact, the predominant inflammatory cell in the lower airways of smokers is the alveolar macrophage rather than the neutrophil. In addition to HNE, other neutrophil proteinases with elastolytic activity and several macrophage elastases have been identified that may contribute to the lung destruction associated with emphysema. The long term goal of this project is to directly determine the role of neutrophil elastase in the pathogenesis of pulmonary emphysema related to cigarette smoking.
The specific aims are to: 1) determine the organization of the mouse neutrophil elastase genomic locus and generate cDNA probes and antibodies to mouse neutrophil elastase; 2) generate lines of mNE-deficient (mNE-/-) mice; 3) use mNE-/- mice to determine the contribution of neutrophil elastase to normal neutrophil functions; and 4) define the capacity of mNE-/- mice vs. normal littermates (mNE+/+) to develop pulmonary emphysema related to cigarette smoking.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL054853-05
Application #
6184318
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1996-06-15
Project End
2001-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
5
Fiscal Year
2000
Total Cost
$227,597
Indirect Cost

  Institution

Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Grumelli, Sandra (2016) Choline Triggers Exacerbations of Chronic Obstructive Pulmonary Disease in Patients Infected with Pseudomonas aeruginosa. Curr Respir Med Rev 12:167-174
Houghton, A McGarry; Rzymkiewicz, Danuta M; Ji, Hongbin et al. (2010) Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 16:219-23
Khatwa, Umakanth A; Kleibrink, Bjoern E; Shapiro, Steven D et al. (2010) MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis. J Leukoc Biol 87:69-77
Peter, Yakov; Comellas, Alejandro; Levantini, Elena et al. (2009) Epidermal growth factor receptor and claudin-2 participate in A549 permeability and remodeling: implications for non-small cell lung cancer tumor colonization. Mol Carcinog 48:488-97
Robbins, Clinton S; Franco, Francesca; Mouded, Majd et al. (2008) Cigarette smoke exposure impairs dendritic cell maturation and T cell proliferation in thoracic lymph nodes of mice. J Immunol 180:6623-8
Kaynar, A Murat; Houghton, A McGarry; Lum, Esther H et al. (2008) Neutrophil elastase is needed for neutrophil emigration into lungs in ventilator-induced lung injury. Am J Respir Cell Mol Biol 39:53-60
Hirahashi, Junichi; Mekala, Divya; Van Ziffle, Jessica et al. (2006) Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25:271-83
Demeo, Dawn L; Mariani, Thomas J; Lange, Christoph et al. (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet 78:253-64
Xu, Jingsong; Tian, Jun; Grumelli, Sandra M et al. (2006) Stage-specific effects of cAMP signaling during distal lung epithelial development. J Biol Chem 281:38894-904
Raptis, Sofia Z; Shapiro, Steven D; Simmons, Pamela M et al. (2005) Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering. Immunity 22:679-91

Showing the most recent 10 out of 16 publications