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Disruption of P-Selectin Signaling Modulates Cell Trafficking and Results in Improved Outcomes after Mouse Warm Intestinal Ischemia and Reperfusion Injury

2005; Wolters Kluwer; Volume: 80; Issue: 6 Linguagem: Inglês

10.1097/01.tp.0000174337.53658.b0

1534-6080

Douglas G. Farmer, Dean M. Anselmo, Xiu Da Shen, Bibo Ke, Ian Carmody, Feng Gao, Charles Lassman, Sue V. McDiarmid, Grey Shaw, Ronald W. Busuttil, Jerzy W. Kupiec‐Weglinski,

Angiogenesis and VEGF in Cancer

Background. This study analyzes the role of T lymphocytes and neutrophils (PMN) in intestinal ischemia and reperfusion injury (IRI) using either P-selectin blockade or elimination. Methods. Using a model of severe mouse warm intestinal IRI, the following groups were performed: group 1: wild type C57BL6 no treatment; group 2: wild type treated with r-PSGL1-Ig; group 3: C57BL6 genetically deficient in P-selectin. Survival was assessed at day 7; intestine was assayed for histopathology, apoptosis, myeloperoxidase (MPO), inflammatory cytokines, hemoxygenase-1 (HO-1), and CD3 lymphocytes. Standard statistical comparison was undertaken. Results. The survival was significantly (P<0.01) improved in the treatment groups: group 1, 50%; group 2, 90%; group 3, 100%. Graded histopathology and crypt apoptosis were improved in groups 2 and 3. MPO and CD3 positive cells were significantly reduced in groups 2 and 3. A significant reduction in inflammatory/Th1-type cytokines was seen in groups 2 and 3 as compared to group 1. Conversely, a significant increase in Th2-type cytokines and HO-1 production was seen selectively in groups 2 and 3. Conclusions. This study demonstrates the importance of P-selectin signaling in warm, murine intestinal IRI in that either the blockade of or the genetic deficiency in P-selectin confers a survival advantage and reduction in tissue injury/inflammation. The mechanism involves a reduction of PMN and CD3 T cell infiltration and an alteration in the cytokine microenvironment in favor of a Th2 profile. These data implicate T lymphocyte as an important regulatory cell in this inflammatory process.