The ability of phagocytes to produce large amounts of oxygen radicals constitutes an important host-defense mechanism against microbial infection. However, the same oxidant-generating machinery also contributes to tissue injury such as in Acute Lung Injury (ALI) resulting from uncontrolled activation of phagocytes. While research on phagocyte NADPH oxidase has produced a great deal of information regarding its activation mechanisms, little is known about the negative regulatory mechanisms that limit phagocyte oxidant production. The objective of Project 2 is to define such negative regulatory mechanisms and explore the potential for dampening lung inflammatory response. Studies are proposed in two substantial specific aims that focus on our recently identified regulatory mechanism by MAP kinase phosphatase 5 (MKPS), which restrains oxidant production by polymorphnuclear neutrophils, thereby decreasing LPS-induced inflammatory vascular injury.
In Aim 1, we will determine how MKP5 regulates PMN oxidant production, which is critical to ALI. The profound negative regulatory effect by MKP5 suggests that p38 MAPK, the target of MKP5, is critical to PMN NADPH oxidase activation. Studies are proposed to test the hypothesis that p38 MAPK is essential for sequential phosphorylation of p47[phox] by a multitude of protein kinases, leading to p47[phox] conformational change and full activation of NADPH oxidase. We will also test the hypothesis that p38 MAPK signaling is further amplified through MK2, a downstream effector and protein kinase that contributes to p47[phox] phosphorylation. The in vivo function of MK2 in ALI and its regulation by MKP5 will be interrogated with the use of MK2 -/- and MKP5 -/- mice.
In Aim 2, we will define the central role of MKP5 in preventing ALI through modulation of PMN and endothelial activation. Using mouse models of lung inflammation, we will test the hypothesis that MKP5 is an essential regulator that reduces proinfiammatory cytokine and chemokine expression, limits PMN infiltration, and dampens PMN oxidant production and oxidant-mediated lung injury. We will also query the possibility that endothelial MKP5 is important in limiting ICAM-1 expression and thus prevents PMN adhesion as well as oxidant-mediated injury. Together, these studies aims to delineate the underlying mechanism for LPS priming of PMN oxidant production, and explore a novel negative regulatory mechanism for its therapeutic potential in controlling ALI.

Public Health Relevance

Bacterial infection may lead to sepsis and result in the loss of lung functions. This serious complication to many infectious diseases is a leading cause of mortality worldwide, and is accompanied by neutrophil mediated injury to the lung tissue. Project 2 aims to understand the intrinsic mechanisms based on negative regulation by a protein phosphatase, thus limiting inflammatory lung injury and offering the opportunity for clinical treatment of inflammatory lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077806-09
Application #
8521344
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$329,972
Indirect Cost
$119,799
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Evans, Colin E; Zhao, You-Yang (2017) Impact of thrombosis on pulmonary endothelial injury and repair following sepsis. Am J Physiol Lung Cell Mol Physiol 312:L441-L451
Du, Xueke; Jiang, Chunling; Lv, Yang et al. (2017) Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling. PLoS One 12:e0180213
Di, Anke; Kiya, Tomohiro; Gong, Haixia et al. (2017) Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages. J Cell Sci 130:735-744
Mittal, Manish; Nepal, Saroj; Tsukasaki, Yoshikazu et al. (2017) Response by Mittal et al to Letter Regarding Article, ""Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury"". Circ Res 121:e87
Cheng, Kwong Tai; Xiong, Shiqin; Ye, Zhiming et al. (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124-4135
Reddy, Sekhar P; Mehta, Dolly (2017) Lung Interstitial Macrophages Redefined: It Is Not That Simple Anymore. Am J Respir Cell Mol Biol 57:135-136
Li, Liping; Sheng, Yue; Li, Wenshu et al. (2017) ?-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q). Cancer Res 77:4116-4126
Evans, Colin E; Zhao, You-Yang (2017) Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension. Adv Exp Med Biol 967:33-45
Tsang, Kit Man; Hyun, James S; Cheng, Kwong Tai et al. (2017) Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1?. Stem Cell Reports 9:796-806
Zhang, Chongxu; Adamos, Crystal; Oh, Myung-Jin et al. (2017) oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading. Am J Physiol Cell Physiol 313:C340-C351

Showing the most recent 10 out of 99 publications