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Abstract
Endotoxemia induces lung injury. We assessed the therapeutic efficacy between triple cytokine (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and IL-6) inhibition (mediated by KCF18 peptide) and single cytokine (TNF-α) inhibition (mediated by SEM18 peptide) on alleviating lung injury in the early phase of endotoxemia. Mice receiving endotoxin (Endo group), endotoxin plus KCF18 (EKCF group), or endotoxin plus SEM18 (ESEM) were monitored and euthanized at 24 h after endotoxin. Our data demonstrated altered lung function (decreases in tidal volume, minute ventilation, and dynamic compliance; and by contrast, increases in airway resistance and end expiration work) and histology (increases in injury scores, leukocyte infiltration, vascular permeability, and tissue water content) in the Endo group with significant protection observed in the EKCF and ESEM groups (all p < 0.05). Levels of inflammation (macrophage activation and cytokine upregulations), oxidation (lipid peroxidation), necroptosis, pyroptosis, and apoptosis in EKCF and ESEM groups were comparable and all were significantly lower than in the Endo group (all p < 0.05). These data demonstrate that single cytokine TNF-α inhibition can achieve therapeutic effects similar to triple cytokines TNF-α, IL-1β, and IL-6 inhibition on alleviating endotoxin-induced lung injury, indicating that TNF-α is the major cytokine in mediating lung injury in the early phase of endotoxemia.
Highlights
The critical role of inflammatory cytokines in mediating systemic inflammation and the development of organ dysfunction and injury in sepsis are established [1,2]
The analysis revealed that the IL-6/IL-6 receptor (IL-6R) proximity ligation assay (PLA) signal intensities in the EKCF and endotoxin plus SEM18 (ESEM) groups were not significantly different (p = 0.190), indicating comparable effects of the KCF18 peptide and the SEM18 peptide on inhibiting endotoxin-induced IL-6/IL-6R binding in lung tissues
The analysis revealed that the IL-6/IL-6R PLA signal intensity in the EKCF group was significantly lower than the Endo group (p = 0.002), indicating the KCF18 peptide can significantly inhibit endotoxin-induced IL-6/IL-6R binding in lung tissues
Summary
The critical role of inflammatory cytokines in mediating systemic inflammation and the development of organ dysfunction and injury (e.g., the lungs) in sepsis are established [1,2]. In the early phase of sepsis, inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are manufactured from infection-triggered immune cells (e.g., macrophages) and stromal cells Pharmaceuticals 2022, 15, 287 cells, endothelial cells, and fibroblasts) through activation of toll-like receptor (TLR) and nuclear factor-κB (NF-κB), and extricated into systemic circulation [3,4]. Clinical data highlight the correlation between the concentrations of TNF-α, IL-1β, and IL-6 and the severity of organ dysfunction/injury in septic patients [5,6]. These cytokines are identified as markers of systemic inflammation and represent potential therapeutic targets against sepsis [7]. With its extrication into circulation in the early phase of sepsis, TNF-α can in turn escalate the systemic inflammatory response [8]. TNF-α is considered a primary modulator of inflammation [8]
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