Abstract
S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.
Highlights
IntroductionAbdominal sepsis is a fatal condition triggered by systemic spread of microbial pathogens, resulting in wide-spread stimulation of the innate immune system
Late administration of ABR-238901 had no effect on neutrophil recruitment, edema and CXC chemokines formation in the lungs of cercal ligation and puncture (CLP) animals
This investigation demonstrates that targeting S100A9 reduces septic of patients sepsis neutrophil poses a huge challenge clinicians
Summary
Abdominal sepsis is a fatal condition triggered by systemic spread of microbial pathogens, resulting in wide-spread stimulation of the innate immune system. Neutrophils are a key component in the innate immune system and excessive activation of neutrophils is known to cause organ dysfunction in sepsis [1,2]. The lung is the most vulnerable organ in abdominal sepsis and the most feared complication of septic lung damage is compromised exchange of oxygen and nutrients in the pulmonary microcirculation. Pulmonary infiltration of neutrophils is known to be a rate-limiting step in sepsis-induced lung injury [3,4]. Targeting specific adhesion molecules has been shown to reduce neutrophil recruitment and tissue damage in septic lungs. Extravascular accumulation of neutrophils is coordinated by secretion of CXC chemokines, including CXCL1 and CXCL2 [5,6]
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