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Combined treatment with a CXCL12 analogue and antibiotics improves survival and neutrophil recruitment and function in murine sepsis
Author(s) -
Guan Shuwen,
Guo Changrun,
Zingarelli Basilia,
Wang Liping,
Halushka Perry V.,
Cook James A.,
Fan Hongkuan
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12382
Subject(s) - sepsis , antibiotics , imipenem , pharmacology , immunology , medicine , in vitro , neutrophile , biology , microbiology and biotechnology , inflammation , biochemistry , antibiotic resistance
Summary Previous studies demonstrated that the CXCL12 peptide analogue CTCE‐0214 (CTCE) has beneficial effects in experimental sepsis induced by caecal ligation and puncture (CLP). We examined the hypothesis that CTCE recruits neutrophils (polymorphonuclear leucocytes; PMN) to the site of infection, enhances PMN function and improves survival of mice in CLP‐induced sepsis with antibiotic treatment. Mice with sepsis ( n = 15) were administered imipenem (25 mg/kg) and CTCE (10 mg/kg) subcutaneously versus vehicle control at designated intervals post‐CLP. CTCE treatment increased PMN recruitment in CLP‐induced sepsis, as evidenced by increased PMN in blood, by 2·4 ± 0·6 fold at 18 hr, 2·9 ± 0·6 fold at 24 hr, and in peritoneal fluid by 2·0 ± 0·2 fold at 24 hr versus vehicle control. CTCE treatment reduced bacterial invasion in blood [colony‐forming units (CFU) decreased 77 ± 11%], peritoneal fluid (CFU decreased 78 ± 9%) and lung (CFU decreased 79 ± 8% versus CLP vehicle). The improved PMN recruitment and bacterial clearance correlated with reduced mortality with CTCE treatment (20% versus 67% vehicle controls). In vitro studies support the notion that CTCE augments PMN function by enhancing phagocytic activity (1·25 ± 0·02 fold), increasing intracellular production of reactive oxygen species (32 ± 4%) and improving bacterial killing (CFU decreased 27 ± 3%). These composite findings support the hypothesis that specific CXCL12 analogues with ancillary antibiotic treatment are beneficial in experimental sepsis, in part, by augmenting PMN recruitment and function.