Growth Arrest-Specific Gene 6 Administration Ameliorates Sepsis-Induced Organ Damage in Mice and Reduces ROS Formation In Vitro.
Livia SalmiFrancesco GavelliFilippo PatruccoMattia BellanPier Paolo SainaghiGian Carlo AvanziLuigi Mario CastelloPublished in: Cells (2021)
Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK (TAM) receptors signaling has shown immunomodulatory activity in sepsis, here we sought to determine whether Gas6 protein injection could mitigate MOF in a cecal slurry mouse model of sepsis. Mice, divided into different groups according to treatment-i.e., placebo (B), ampicillin (BA), Gas6 alone (BG), and ampicillin plus Gas6 (BAG)-were assessed for vitality, histopathology and cytokine expression profile as well as inducible nitric oxide synthase (iNOS), ALT and LDH levels. BAG-treated mice displayed milder kidney and lung damage and reduced levels of cytokine expression and iNOS in the lungs compared to BA-treated mice. Notably, BAG-treated mice showed lower LDH levels compared to controls. Lastly, BAG-treated cells of dendritic, endothelial or monocytic origin displayed reduced ROS formation and increased cell viability, with a marked upregulation of mitochondrial activity. Altogether, our findings indicate that combined treatment with Gas6 and antibiotics ameliorates sepsis-induced organ damage and reduces systemic LDH levels in mice, suggesting that Gas6 intravenous injection may be a viable therapeutic option in sepsis.
Keyphrases
- acute kidney injury
- high fat diet induced
- intensive care unit
- oxidative stress
- nitric oxide synthase
- septic shock
- mouse model
- immune response
- room temperature
- diabetic rats
- poor prognosis
- newly diagnosed
- dna damage
- nitric oxide
- cell death
- metabolic syndrome
- copy number
- insulin resistance
- carbon dioxide
- clinical trial
- endothelial cells
- small molecule
- dendritic cells
- gene expression
- drug induced
- ejection fraction
- dna methylation
- cardiovascular events
- skeletal muscle
- cell proliferation
- induced apoptosis
- coronary artery disease
- high dose
- inflammatory response
- low dose
- reactive oxygen species
- ultrasound guided
- amino acid
- prognostic factors
- smoking cessation
- cell cycle arrest
- protein protein
- combination therapy