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Int J Mol Sci ; 22(23)2021 Nov 29.
Article in English | MEDLINE | ID: covidwho-1561718


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.

Acute Lung Injury/prevention & control , Calgranulin B/metabolism , Neutrophil Infiltration/drug effects , Sepsis/complications , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Chemokines, CXC/metabolism , Drug Evaluation, Preclinical , Interleukin-6/metabolism , Lung/metabolism , Male , Mice, Inbred C57BL , Sepsis/immunology , Sepsis/metabolism
Int J Mol Sci ; 22(14)2021 Jul 06.
Article in English | MEDLINE | ID: covidwho-1502438


Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.

Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Extracellular Traps/immunology , Neutrophils/immunology , Neutrophils/pathology , Animals , Disease Progression , Extracellular Traps/physiology , Humans , Neoplasm Metastasis/immunology