Importance of Defining Pathways for Recruitment and Turnover of Leukocytes in Inflammation -Inflammation is an immune cell response that leads to the accumulation of white blood cells (leukocytes) at sites of infecfion, injury or irritation. The extravasation of polymorphonuclear leukocytes (PMNs), primarily neutrophils, through selecfin and integrin-mediated pathways, to a site of infiammation is followed by the emigrafion of monocytes/macrophages (Fig. 1). Released granule proteins from activated neutrophils induce further emigrafion of inflammatory cells to such sites, involving selectins, P2-integrins and formyl-peptide receptors. Accompanying changes in the chemokine network create a favorable local microenvironment for extravasation of addifional inflammatory monocytes. Thus, for this positive feedback loop to end, inflammation must be resolved by the removal of the infiammatory insult (bacteria or wound detritus), along with eventual removal of the emigrated inflammatory cells. While resolution is clearly the key to limifing tissue injury in all types of inflammation, it is remarkable that so little is known about the mechanism of cellular turnover and the factors promofing the resolution of inflammation. It has been thought that resolution occurs through spontaneous apoptosis of neutrophils and their subsequent phagocytosis and engulfment(4). Surprisingly, however, neutrophil apoptosis in vivo is not a major factor in regulating their numbers in inflammation. Unlike T cells, which accumulate following perturbation of pathways involved in leukocyte apoptosis(5,6), inhibition of neutrophil apoptosis does not greafiy alter neutrophil turnover in vivo, but the mechanism(s) of targeting viable neutrophils for removal is unknown (5-8). Thus, neutrophil turnover is possibly regulated by nonapoptotic factors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL085607-06
Application #
8112971
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2011
Total Cost
$541,626
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Panicker, Sumith R; Mehta-D'souza, Padmaja; Zhang, Nan et al. (2017) Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice. Blood 130:181-191
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Rahman, H N Ashiqur; Wu, Hao; Dong, Yunzhou et al. (2016) Selective Targeting of a Novel Epsin-VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis. Circ Res 118:957-969
Liu, Zhenghui; Zhang, Nan; Shao, Bojing et al. (2016) Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. J Biol Chem 291:1441-7
Brazil, Jennifer C; Sumagin, Ronen; Cummings, Richard D et al. (2016) Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. Am J Pathol 186:297-311
Chen, Wei-Sheng; Cao, Zhiyi; Sugaya, Satoshi et al. (2016) Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat Commun 7:11302
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2016) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 126:1607
Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126:2254-66

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