Beneficial effects of CCL8 inhibition at lipopolysaccharide-induced lung injury
Asieh Naderi,
Elena Farmaki,
Bernardo Chavez,
Chao Cai,
Vimala Kaza,
Youwen Zhang,
Elham Soltanmohammadi,
Nina Daneshvar,
Ioulia Chatzistamou,
Hippokratis Kiaris
Affiliations
Asieh Naderi
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Elena Farmaki
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Bernardo Chavez
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Chao Cai
Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Vimala Kaza
Peromyscus Genetic Stock Center, University of South Carolina, Columbia, SC, USA
Youwen Zhang
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Elham Soltanmohammadi
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Nina Daneshvar
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
Ioulia Chatzistamou
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
Hippokratis Kiaris
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA; Peromyscus Genetic Stock Center, University of South Carolina, Columbia, SC, USA; Corresponding author
Summary: CCL8 (MCP-2) is a chemoattractive cytokine associated with various immune-related pathologies. Recent studies show that CCL8 is significantly stimulated during acute respiratory distress syndrome in severely ill patients with COVID-19, making the inhibition of CCL8 activity a promising treatment. Lipopolysaccharide (LPS)-induced lung injury was evaluated in mice using a neutralizing antibody (1G3E5) against human CCL8. Pharmacokinetic studies indicated that following IP administration, 1G3E5 was sustained at higher levels and for a longer period compared to IV administration. CCL8 expression in the lungs was not enhanced by LPS, but CCR2 and CCR5 receptors were significantly stimulated. 1G3E5-mediated inhibition of CCL8 was associated with the reduction of pulmonary inflammation and suppression of various pro-inflammatory cytokines. These results point to a previously unrecognized, permissive role for CCL8 in mediating cytokine induction and ultimately sustaining inflammation. Disruption of CCL8 activity may provide a strategy for mitigating pulmonary inflammation during lung injury when related to abnormal cytokine induction.
