HMGB1: A Potential Target of Nervus Vagus Stimulation in Pediatric SARS-CoV-2-Induced ALI/ARDS

Abstract

From the start of pandemics, children were described as the ones who were less affected by SARS-Cov-2 or COVID-19, which was mild in most of the cases. However, with the growing vaccination rate of the adult population, children became more exposed to the virus and more cases of severe SARS-CoV-2-induced ARDS are being diagnosed with the disabling consequences or lethal outcomes associated with the cytokine storm. Thus, we do hypothesize that some of the children could benefit from nervus vagus stimulation during COVID-19 ARDS through the inhibition of HMGB1 release and interaction with the receptor, resulting in decreased neutrophil accumulation, oxidative stress, and coagulopathy as well as lung vascular permeability. Moreover, stimulation through alpha-7 nicotinic acetylcholine receptors could boost macrophage phagocytosis and increase the clearance of DAMPs and PAMPs. Further rise of FGF10 could contribute to lung stem cell proliferation and potential regeneration of the injured lung. However, this stimulation should be very specific, timely, and of proper duration, as it could lead to such adverse effects as increased viral spread and systemic infection, especially in small children or infants due to specific pediatric immunity state and anatomical features of the respiratory system.

Association between serum HMGB1 elevation and early pediatric acute respiratory distress syndrome: a retrospective study of pediatric living donor liver transplant recipients with biliary atresia in China

“…Moreover, in this study, the confounding factors were not adjusted during the perioperative period. Pediatric patients are more susceptible to surgical stress, ischemia-reperfusion, and the effects of anesthesia drugs and long-term mechanical ventilation because of the specific pediatric immunity state and anatomical features of the respiratory system [ 17 ]. As a result, children are more vulnerable to perioperative lung injury than adults.…”

“…In addition, extensive studies have demonstrated that plasma HMGB1 level is a sensitive indicator of acute respiratory distress syndrome (ARDS) [ 14 ]. HMGB1 is a central mediator of lethal inflammation and could be a potential target for innovative therapeutic strategies for COVID-19 [ 15 , 16 ], even in the pediatric field [ 17 ].…”

Effect of stimulated platelets in COVID-19 thrombosis: Role of alpha7 nicotinic acetylcholine receptor

“…This pathway bridges the autonomic nervous system and immune system. Recently, the alleviating effect of COVID-19-induced hyperinflammation has been widely described in several studies (115,117,(121)(122)(123). Under direct activation of the afferent vagal nerve, the main neurotransmitter ACh is released which further stimulates α7nAChR (124,125) resulting in an anti-inflammatory response.…”

Echinacea Polyphenols Inhibit NLRP3-Dependent Pyroptosis, Apoptosis, and Necroptosis via Suppressing NO Production during Lipopolysaccharide-Induced Acute Lung Injury

“…PANoptosis is a complex form of inflammatory programmed cell death (PCD) pathway that involves pyroptosis, apoptosis, and necroptosis, whereas it cannot be characterized by any of these three PCD pathways alone. , PANoptosis has been elucidated in a variety of conditions ranging from normal development to microbial infectious, autoimmune diseases, cytokine storm, and cancer. Previous studies have shown that PANoptosis was closely related to lung injury. , During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients develop systemic symptoms of varying severity and induce PANoptosis, leading to further exacerbation of the pulmonary cytokine storm, and COVID-19-associated pneumonia can progress to ARDS. ,, Because of the complexity of PANoptosis, the treatment maybe fails if three PCDs in PANoptosis cannot be simultaneously inhibited to prevent the compensatory activation of other pathways. However, no research focused on a certain drug or treatment to simultaneously inhibit the three arms of PANoptosis process in ALI.…”

“…3,15 During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients develop systemic symptoms of varying severity and induce PANoptosis, leading to further exacerbation of the pulmonary cytokine storm, and COVID-19associated pneumonia can progress to ARDS. 5,16,17 Because of the complexity of PANoptosis, the treatment maybe fails if three PCDs in PANoptosis cannot be simultaneously inhibited to prevent the compensatory activation of other pathways.…”