L-selectin shedding in sepsis limits leukocyte mediated microvascular injury at remote sites

• Published in: Surgery Vol. 145; no. 4; pp. 384 - 391
• Main Authors: Ferri, Lorenzo E., MD, PhD, Chia, Shea, MD, Benay, Cassandre, BSc, Giannias, Betty, BSc, Christou, Nicolas V., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.04.2009; Elsevier
• Subjects: Animals; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; Capillary Permeability - immunology; Cell Adhesion; Endothelial Cells - physiology; Fluorescein-5-isothiocyanate; General aspects; Human bacterial diseases; Hydroxamic Acids - pharmacology; Infectious diseases; Inflammation - drug therapy; L-Selectin - drug effects; L-Selectin - metabolism; L-Selectin - physiology; Lipopolysaccharides; Male; Medical sciences; Mice; Neutrophils - physiology; Random Allocation; Scrotum - blood supply; Sepsis - immunology; Sepsis - physiopathology; Surgery; Tumor Necrosis Factor-alpha - metabolism; Leukocyte; Cell adhesion molecule; Trauma; Bacteremia; L Selectin; Infection; Medicine; Sepsis syndrome; Microcirculation; Treatment; Surgery; Bacteriosis; Limit; Lesion
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2008.12.011

Background Increased soluble L-selectin levels have been shown to attenuate local inflammation-mediated microvascular leakage, and failure to generate high levels has been associated with increased risk of acute respiratory distress syndrome in septic patients. We hypothesized that failure to shed L-selectin in systemic inflammation would result in increased local inflammation-induced leukocyte adherence and microvascular leakage. Methods Using intraperitoneal lipopolysaccharide (LPS) or control bicarbonate buffered saline (BBS) and intrascrotal TNFα or BBS, mice were randomized to systemic inflammation (LPSip + BBSis), local inflammation (BBSip + TNFis), both (LPSip + TNFis), or control (BBSip+BBSis). Furthermore, mice received intraperitoneal L-selectin Sheddase inhibitor (Ro31-9790) or control vector. With intravital microscopy on cremaster muscle, we measured leukocyte-endothelial cell interactions and microvascular leakage (permeability index). Surface L-selectin was measured by flow cytometry (MCF). Results Without Ro31-9790, systemic inflammation attenuated increases induced by local inflammation in leukocyte adherence and vascular leakage. Ro31-9790 significantly increased adherence and leakage in systemic and systemic + local inflammation. L-selectin was shed progressively by increasing degrees of inflammation. Ro31-9790 limited this shedding of L-selectin. Conclusion In systemic inflammation, L-selectin shedding is required to limit local inflammation-mediated leukocyte adherence and microvascular leakage. Failure to shed L-selectin may increase leukocyte-mediated end-organ injury in septic patients.