Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis.

Abstract

Sepsis is an acute inflammatory condition that can result in multiple organ failure and acute lung injury. Growth arrest-specific protein 6 (Gas6) is a broad regulator of the innate immune response involved with the nuclear factor κB signaling pathway. We hypothesized that Gas6 could have a protective role in attenuating the severity of acute lung injury and sepsis. Male mice were subjected to sepsis by cecal ligation and puncture (CLP) after which recombinant murine Gas6 (rmGas6; 5 μg/mouse) or normal saline (vehicle) was administered intravenously. Blood and lung tissues were collected at 20 h after CLP for various measurements. Treatment with rmGas6 significantly reduced serum levels of the injury markers aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as proinflammatory cytokines interleukin 6 (IL-6) and IL-17, compared with the vehicle group (P < 0.05). The parenchyma of the lungs damaged by CLP was attenuated by rmGas6 treatment. Lung mRNA levels of tumor necrosis factor α, IL-1β, IL-6, IL-17, and macrophage inflammatory protein 2 (MIP-2) were decreased by 60%, 86%, 82%, 93%, and 82%, respectively, with rmGas6 treatment as determined by real-time reverse transcriptase-polymerase chain reaction (P < 0.05). The degradation of IκB-α induced by CLP in the lungs was inhibited by rmGas6 treatment. The number of neutrophils and myeloperoxidase activity in the lungs were significantly reduced in the rmGas6 group. Moreover, rmGas6 reduced the in vitro migration of differentiated human promyelocytic HL60 cells by 64%. Finally, the 10-day survival rate of mice subjected to CLP was increased from 31% in the vehicle group to 67% in the rmGas6 group (P < 0.05). Thus, Gas6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury.

• Authors: Matthew D Giangola, Weng-Lang Yang, Salil R Rajayer, Jeffrey Nicastro, Gene F Coppa, Ping Wang
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 40 Issue 6 Pg. 485-91 (Dec 2013) ISSN: 1540-0514 [Electronic] United States
• PMID: 23881260 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Biomarkers
• Chemokines
• Cytokines
• I-kappa B Proteins
• Inflammation Mediators
• Intercellular Signaling Peptides and Proteins
• NFKBIA protein, human
• Nfkbia protein, mouse
• Recombinant Proteins
• growth arrest-specific protein 6
• NF-KappaB Inhibitor alpha
• Peroxidase

Topics

• Acute Lung Injury (etiology, immunology, pathology, prevention & control)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Biomarkers (blood)
• Cells, Cultured
• Chemokines (biosynthesis)
• Cytokines (biosynthesis, blood)
• Drug Evaluation, Preclinical (methods)
• I-kappa B Proteins (metabolism)
• Immune System Diseases
• Inflammation Mediators (metabolism)
• Intercellular Signaling Peptides and Proteins (pharmacology, therapeutic use)
• Leukocyte Disorders
• Lung (immunology)
• Male
• Mice
• NF-KappaB Inhibitor alpha
• Peroxidase (metabolism)
• Recombinant Proteins (pharmacology, therapeutic use)
• Sepsis (complications)