) The project will analyze the role of the neutrophil/monocyte serine proteases, elastase, cathepsin-G and proteinase-3, and their specific inhibitors, alpha- 1-antitrypsin and especially MNEI (monocyte/neutrophil elastase inhibitor), in infection and inflammation of COPD. The hypothesis to be evaluated is that excess of the proteases in inflammatory lung fluids contributes to disease progression, not only by inducing inflammation and injury, but also importantly by targeting and destroying innate anti-microbial pulmonary defense molecules. Based largely on the investigators recent findings, the investigators hypothesize that an important innate defense molecule targeted by the proteases, and protected by MNEI, is surfactant protein-A (SP-A), an opsonin and activating agent, known to enhance uptake and clearance of microbes by resident pulmonary macrophages. Studies are proposed in a mouse model of excess neutrophil/monocyte protease activity, which the investigators will generate by targeting the mnei gene. Mnei-A def deficient mice will be compared to wildtype mice for their ability to clear pulmonary infections with Streptococcus pneumoniae and nontypeable Haemophilus influenzae, significant infectious agents in chronic bronchitits. Inflammatory parameters (neutrophil influx, free protease, SP-A levels, cytokines, chemokines) will also be compared. Using a complementary human in vitro system, the investigators will compare inflammatory lung fluids (BAL supernatants) of COPD patients with lung fluids of normal healthy non-smokers and smokers, for their ability to enhance uptake of S. pneumoniae and H. influenzae by normal macrophages. The investigators will examine also the effect of exogenous protease on bacterial uptake enhancing activity (including SP-A). Clarifying the role of elastase, cathepsin-G and proteinase-3 in disease progression of COPD is important, among other reasons, because therapeutic modalities are now feasible and could be delivered to the patients if the underlying pathological processes were understood.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066548-04
Application #
6619872
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S2))
Program Officer
Croxton, Thomas
Project Start
2000-09-29
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$425,700
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
El Ouaamari, Abdelfattah; Dirice, Ercument; Gedeon, Nicholas et al. (2016) SerpinB1 Promotes Pancreatic ? Cell Proliferation. Cell Metab 23:194-205
Burgener, Sabrina S; Baumann, Mathias; Basilico, Paola et al. (2016) Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1. Biol Chem 397:897-905
Hou, Lifei; Cooley, Jessica; Swanson, Richard et al. (2015) The protease cathepsin L regulates Th17 cell differentiation. J Autoimmun 65:56-63
Zhao, Picheng; Hou, Lifei; Farley, Kalamo et al. (2014) SerpinB1 regulates homeostatic expansion of IL-17+ ?? and CD4+ Th17 cells. J Leukoc Biol 95:521-30
Stolley, J Michael; Gong, Dapeng; Farley, Kalamo et al. (2012) Increased surfactant protein D fails to improve bacterial clearance and inflammation in serpinB1-/- mice. Am J Respir Cell Mol Biol 47:792-9
Farley, Kalamo; Stolley, J Michael; Zhao, Picheng et al. (2012) A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation. J Immunol 189:4574-81
Cooley, J; Sontag, M K; Accurso, F J et al. (2011) SerpinB1 in cystic fibrosis airway fluids: quantity, molecular form and mechanism of elastase inhibition. Eur Respir J 37:1083-90
Gong, Dapeng; Farley, Kalamo; White, Mitchell et al. (2011) Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection. J Infect Dis 204:592-600
Benarafa, Charaf; LeCuyer, Tessa E; Baumann, Mathias et al. (2011) SerpinB1 protects the mature neutrophil reserve in the bone marrow. J Leukoc Biol 90:21-9
Davies, Philip L; Spiller, O Brad; Beeton, Michael L et al. (2010) Relationship of proteinases and proteinase inhibitors with microbial presence in chronic lung disease of prematurity. Thorax 65:246-51

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