Journal of Translational Critical Care Medicine

: 2021  |  Volume : 3  |  Issue : 1  |  Page : 14-

Endogenous Sulfur Dioxide, a Novel Gaseous Transmitter Involved in the Regulation of Inflammatory Responses

Siyao Chen1, Junbao Du2,  
1 Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, China
2 Department of Pediatrics, Peking University First Hospital; Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China

Correspondence Address:
Dr. Junbao Du
Xi-An Men Street No 1, West District, Department of Pediatrics, Peking University First Hospital, Beijing - 100034


Endogenous sulfur dioxide (SO2) used to be perceived as a notorious, toxic pollutant of the atmosphere. However, recently several studies revealed that in vivo generated mainly from sulfur-containing amino acids, SO2 serves as an essential novel gasotransmitter involved in the regulation of extensive biological activities. Several studies indicate that endogenous SO2 protects against inflammation by inhibiting the production of inflammatory mediators via different molecular pathways. The present review, therefore, summarized the anti-inflammatory effect of endogenous SO2 and its molecular mechanisms.

How to cite this article:
Chen S, Du J. Endogenous Sulfur Dioxide, a Novel Gaseous Transmitter Involved in the Regulation of Inflammatory Responses.J Transl Crit Care Med 2021;3:14-14

How to cite this URL:
Chen S, Du J. Endogenous Sulfur Dioxide, a Novel Gaseous Transmitter Involved in the Regulation of Inflammatory Responses. J Transl Crit Care Med [serial online] 2021 [cited 2021 Nov 30 ];3:14-14
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In mammals, endogenous sulfur dioxide (SO2) plays a crucial role in the pathogenesis of hypertension, pulmonary arterial structural remodeling, cardiac ischemia-reperfusion (I/R) damage, atherosclerosis, vascular calcification, myocardial hypertrophy, cardiac fibrosis, myocardial infarction, acute lung injury (ALI) and intestine colitis.[1],[2],[3],[4],[5],[6],[7],[8] The mechanisms probably involving its antioxidant and anti-inflammatory capacity in addition to its regulatory role in the pathogenesis of macrophage inflammation, adipocyte inflammation, mast cell degranulation, and lipid metabolism.[9],[10],[11],[12],[13],[14],[15],[16] The physiological and pathophysiological significance in mammals, therefore, is attracting wide interest. Here, we reviewed the impact of endogenous SO2 on inflammatory responses in different systems of mammals.

 Endogenous Generation, Distribution and Pathophysiologic Effects of SO2

Endogenous SO2 could be synthesized in mammals through the oxidation of hydrogen sulfide (H2S) and is mostly generated from sulfur-containing amino acids, which are catalyzed to form cysteine sulfonate.[17] Transformed to β-sulfinyl pyruvate by aspartate aminotransferase (AAT), L-cysteine sulfinate eventually spontaneously decomposes to form pyruvate, releasing SO2.[18],[19] SO2 is eventually oxidized to sulfate dissolved in urine and discharged out of the system. Additionally, SO2 is synthesized in activated neutrophils when H2S is catalyzed by NADPH oxidase, among other enzymes.[20] Apart from endogenous generation, SO2 may be obtained through exogenous food absorption, including fruits, vegetables, seafood, beverages, and a few meat products.

The endogenous SO2 generating system is identified in various tissues including heart, brain, lung, vasculatures, stomach, liver, intestine, cerebral gray matter, pancreas, renal medulla, renal cortex, spleen, and kidney. Previously, it was reported that endogenous SO2, which played an important role in the physiologic process of the cardiovascular system, could be generated in the cardiac tissues.[21] AAT generation in endothelium and vascular smooth muscle cells adjacent to the endothelial layer is abundant. The level of SO2 is highest in the stomach. In the left ventricle, the activity and mRNA expression of AAT are high compared to other tissues.[22]

Physiologically, SO2 exerts a negative inotropic effect in cardiac tissues, dilates vasculatures, suppresses proliferation of smooth muscle cells in the blood vessels as well as assists in maintaining intact vascular structure, significantly regulating and impacting the cardiovascular system.[16],[21],[23],[24]

Aberrant SO2 synthesis in vivo could contribute to various diseases in the cardiovascular system including but not being limited to ALI, pulmonary arterial hypertension, hypertension, atherosclerosis, vascular calcification, myocardial hypertrophy, ISO-induced myocardial injury, and I/R induced myocardial injury.[6],[16],[25],[26] However, these diseases could be attenuated by SO2 donors, implying that SO2 vigorously participated in cardiovascular pathophysiology. Others report that endogenous SO2 regulates cardiovascular pathophysiology via molecular signaling mechanisms associated with modifying cysteine residues through sulfenylation, converting the free sulfhydryl groups (-SH) into sulfenic acid (-SOH). In addition, SO2 sulfenylates p65 at cysteine-38 and suppresses the activation of the NF-кB pathway. Moreover, it sulfenylates Smad3 and suppresses Smad3 activation.[26] With characteristics of swift dispersion, continuous generation, free passage through the cell membrane, and a wide range of regulatory effects in vivo, endogenous SO2 is established as a novel gasotransmitter in mammals.[27]

 Endogenous SO2 Inhibits Inflammatory Responses in the Cardiovascular System

Inflammation is closely related to the pathogenesis of cardiovascular diseases. Inflammation orchestrates the pathogenic cascade of cardiovascular damage often initiated by activated NF-κB.[28],[29],[30],[31],[32] Both interleukin-1 (IL-1) and IL-6 are inflammatory factors generated by NF-κB activation.[33],[34],[35],[36] Meanwhile, to protect against inflammatory insult and stimulate the healing of wounds, cytokines with anti-inflammatory effects such as IL-10 are generated.[37],[38] It was reported that synthesized in macrophage, SO2 played a potent role in the activation of macrophage.[11] In macrophages, the NF-κB pathway is activated when AAT2 is knocked down. However, upregulation of the endogenous SO2 pathway reversed the activation of NF-κB caused by AAT2 knockdown. On the other hand, when insulted by Ang II administration, the activated NF-κB and inflammatory responses in cardiac tissues of the mouse model were rescued by the overexpression of AAT2, establishing that inflammation in the heart tissues of mammals could be attenuated by endogenous SO2.[11]

SO2 supplementation reduced the levels of inflammatory cytokines including intercellular adhesion molecule-1 (ICAM-1) and NF-кB, thereby exerting protective effects against inflammation. SO2 supplementation could downregulate the pathway of TLR4/NLRP3 and inhibit inflammation in cardiac tissues caused by sepsis.[3] In hypoxic hypertensive rats, the levels of inflammatory cytokines including NF-кB and ICAM-1 were reduced when administrated with an SO2 donor.[39] Inflammation is involved in pulmonary artery hypertension (PAH).[40],[41],[42] Endogenous SO2 could downregulate key inflammation cytokines including ICAM-1 and NF-κB in a rat model of PAH, suggesting that SO2 protects against pulmonary hypertension via inhibiting inflammation.

Interestingly, AAT was inactivated by sulfhydration of AAT1/2, the SO2 generating enzymes, and the synthesis of endogenous SO2 was downregulated. In the case of aberrant endogenous H2S/CSE generation, endogenous SO2 pathway could be upregulated to compensate for it, thus protecting against inflammation in the endothelium. Knockdown of H2S/CSE in rat pulmonary arterial endothelium resulted in inflammation, which could be further fueled by HDX, indicating that to defend the stability of pulmonary arterial endothelial cells, the endogenous gasotransmitter, endogenous SO2 could compensate the reduced H2S pathway.[25]

 Endogenous SO2 Inhibits Inflammatory Responses in Acute Lung Injury Via p65 Sulphenylation

In a rat model of lipopolysaccharide (LPS)-induced ALI, levels of IL-1 and IL-6 were reduced by the administration of SO2 donor, but levels of IL-10 were promoted by SO2 donor. In the rat model of LPS-induced ALI, inflammation was significantly attenuated by endogenous SO2 via the regulation of p-ERK, Raf-1, and MEK-1. The molecular mechanisms underlying LPS-induced ALI possibly involved the downregulated endogenous SO2 systems.[10] The administration of the SO2 donor markedly attenuated ALI subsequently to I/R in the limbs, which was markedly aggravated by HDX. The changes of plasma inflammatory cytokine levels and the changes of inflammatory responses in the respiratory system were consistent, suggesting that the downregulated SO2 synthesis participated in the regulation of ALI after the insult of I/R in a rat model.[43]

In rats with ALI, inflammation was inhibited by endogenous SO2 via posttranscriptional modification, p65 sulphenylation at Cys 38.[44] Activation of p65 was inhibited irrespectively by SO2 pretreatment and AAT1 overexpression. However, at the cellular level, the knockdown of AAT1 induced the activation of p65 and subsequent inflammatory cascades similar to OA insult. OA increased nuclear translocation of NF-κB and its binding activity of DNA, contributing to the subsequent inflammatory cascades in the cellular level, which could be reversed by SO2 pretreatment.

 Endogenous SO2 Ameliorates Inflammation in Colitis Via Inhibiting Nuclear Factor Kappa B and Inflammasome Activation

In Wistar rats with colitis caused by the insult of 2,4,6-trinitrobenzene sulfonic acid (TNBS), the endogenous SO2 pathway was markedly downregulated. TNBS insult resulted in an increased NF-κB and the inflammasome activation, which could be reversed by SO2 donor.[12] Thus, the endogenous SO2 ameliorated colitis at least via inhibiting inflammation.

 Endogenous SO2 Synthesized in Adipocytes Demonstrates Potent Anti-inflammatory Effects

Zhang et al. revealed that the SO2 generating system existed in a variety of adipose tissues.[9] The endogenous SO2 level was markedly elevated by the overexpression of AAT1, and inflammatory cytokine secretion from adipocytes was subsequently inhibited. On the contrary, SO2 generation was downregulated by the knockdown of AAT1, and the secretion of pro-inflammatory cytokines stimulated by tumor necrosis factor-α (TNF-α) subsequently boosted. The underlying mechanism involved the phosphorylation of p65 and IκBα caused by TNF-α insult which was suppressed by the overexpression of AAT1. And SO2 donor reversed the activation of NF-κB, which was promoted by the knockdown of AAT1 [Figure 1].[9]{Figure 1}


The gasotransmitters vigorously participate in a broad range of biological activities in mammals, including the pathophysiologic process of inflammation.[9],[11],[12],[39],[44] Reviews on the molecular mechanisms by which the novel gasotransmitter, endogenous SO2, regulates inflammatory responses in mammals were scarce. The present review summarized that in the cardiovascular system, the endogenous SO2 potently protects against inflammation at least via the inhibition of NF-κB and the TLR4/NLRP3 signaling pathway.[3] In addition, to inhibit inflammation in pulmonary arterial endothelial cells, the gasotransmitter SO2 compensates the insufficiency of H2S under certain situations. In the respiratory system, endogenous SO2 inhibits inflammatory responses in ALI via p65 sulphenylation. Moreover, inflammation was significantly attenuated by endogenous SO2 via the regulation of p-ERK, Raf-1, and MEK-1 in rats with LPS-induced ALI. In the gastrointestinal system, SO2 ameliorates inflammation in colitis caused by TNBS insult via inhibiting NF-κB and inflammasome activation. In addition, the endogenous SO2 system could be generated in adipocyte and antagonize inflammation via inhibiting the activation of NF-κB.[9]

Elaborating on the impact of endogenous SO2 pathway on the inflammation in different mammal systems enriches the pathophysiologic process of inflammation. Also, the discovery of the novel gasotransmitter SO2 provides the potential measures for the prevention and control of different diseases, which merits further investigation.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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