4.6 Article

Platelet Endothelial Cell Adhesion Molecule (PECAM/CD31) Blockade Modulates Neutrophil Recruitment Patterns and Reduces Infarct Size in Experimental Ischemic Stroke

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AMERICAN JOURNAL OF PATHOLOGY
卷 192, 期 11, 页码 1619-1632

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ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2022.07.008

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资金

  1. NIH Cancer Center Support Grant [P30 CA060553]
  2. NIH [R25 NS070695, T32 GM142604, R35 HL155652]

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The infiltration of polymorphonuclear leukocytes (PMNs) in ischemia-reperfusion injury (I/RI) is considered a critical component of inflammatory damage following ischemic stroke. Blocking platelet endothelial cell adhesion molecule-1 (PECAM) can alter the distribution of PMNs, reduce infarct volume, and suggest the potential therapeutic benefit of regulating the timing and pattern of leukocyte infiltration.
The infiltration of polymorphonuclear leukocytes (PMNs) in ischemia-reperfusion injury (I/RI) has been implicated as a critical component of inflammatory damage following ischemic stroke. However, suc-cessful blockade of PMN transendothelial migration (TEM) in preclinical studies has not translated to meaningful clinical outcomes. To investigate this further, leukocyte infiltration patterns were quanti-fied, and these patterns were modulated by blocking platelet endothelial cell adhesion molecule-1 (PECAM), a key regulator of TEM. LysM-eGFP mice and microscopy were used to visualize all myeloid leukocyte recruitment following ischemia/reperfusion. Visual examination showed heterogeneous leukocyte distribution across the infarct at both 24 and 72 hours after I/RI. A semiautomated process was designed to precisely map PMN position across brain sections. Treatment with PECAM function -blocking antibodies did not significantly affect total leukocyte recruitment but did alter their distri-bution, with more observed at the cortex at both early and later time points (24 hours: 89% PECAM blocked vs. 72% control; 72 hours: 69% PECAM blocked vs. 51% control). This correlated with a decrease in infarct volume. These findings suggest that TEM, in the setting of I/RI in the cere-brovasculature, occurs primarily at the cortical surface. The reduction of stroke size with PECAM blockade suggests that infiltrating PMNs may exacerbate I/RI and indicate the potential therapeutic benefit of regulating the timing and pattern of leukocyte infiltration after stroke. (Am J Pathol 2022, 192: 1619-1632; https://doi.org/10.1016/j.ajpath.2022.07.008)

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