The innate immune system plays critical roles in maintaining a healthy lung and in shaping the adaptive immune response to challenge. As for most biological processes, the extent, pattern, and duration of inflammation are controlled by a balance between positive and negative factors. Our preliminary data indicates that stromelysin-2 (MMP-10), a member of the matrix metalloproteinase gene family, functions to govern the extent of inflammation in the lung by controlling the influx and activation state of infiltrated macrophages. In response to toxic injury or bacterial infection, stromelysin-2 expression is induced, and when production peaked in wildtype mice, MmpIO'^'mice died or were moribund. The difference in mortality between wildtype and null mice was not associated with a difference in bacterial clearance. Rather, MmpW'' had more severe inflammation in lung tissue than did wildtype mice. Furthermore, data from cell culture models indicate that most stromelysin-2 expression is produced by infiltrated macrophages, and compared to cells from infected wildtype mice, macrophages from MmpIO'''mice expressed reduced levels of some immunosuppressive factors, such as IL-10. Gene expression arrays studies in other models (smoke exposure) suggest that stromelysin-2 is needed for activation of several immune pathways. Based on these data, we hypothesize that stromelysln-2 functions to moderate lung inflammation and immune processes by controlling the activation state of infiltrated macrophages and, in turn, downstream Immune processes. To study the role of stromelysin-2 in more detail, we propose to 1) identify the subpopulation of macrophages and the activation status affected by stromelysin-2;2) determine the relative roles of epithelial- and macrophage-derived stromelysin-2;and 3) assess the role of stromelysin-2 in governing the macrophage response to bacterial infection. This project complements the overall theme of this Program to explore mechanisms linking innate immunity in the lung to downstream adaptive responses, and several interactions are proposed with the other three projects and both scientific cores.

Public Health Relevance

These studies will characterize a novel, fundamental mechanism controlling macrophage activation and the resolution of inflammation. Knowledge from this work may provide an effective strategy to limit inflammationassociated damage not only in lung, but in all tissues.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098067-05
Application #
8701348
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$536,930
Indirect Cost
$96,944
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
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Sheih, A; Parks, W C; Ziegler, S F (2016) GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen. Mucosal Immunol :

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