Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis.

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.

• Authors: Zhiyi Ding, Feifei Du, Richard Garland Averitt V, Gabriel Jakobsson, Carl-Fredrik Rönnow, Milladur Rahman, Alexandru Schiopu, Henrik Thorlacius
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 23 (Nov 29 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34884728 (Publication Type: Journal Article)

Chemical References

• ABR-238901
• Calgranulin B
• Chemokines, CXC
• Interleukin-6
• S100A9 protein, mouse
• Sulfonamides
• interleukin-6, mouse

Topics

• Acute Lung Injury (etiology, metabolism, prevention & control)
• Animals
• Calgranulin B (metabolism)
• Chemokines, CXC (metabolism)
• Drug Evaluation, Preclinical
• Interleukin-6 (metabolism)
• Lung (metabolism)
• Male
• Mice, Inbred C57BL
• Neutrophil Infiltration (drug effects)
• Sepsis (complications, immunology, metabolism)
• Sulfonamides (pharmacology, therapeutic use)