Hydrogen Sulfide as Potential Regulatory Gasotransmitter in Arthritic Diseases

Abstract

The social and economic impact of chronic inflammatory diseases, such as arthritis, explains the growing interest of the research in this field. The antioxidant and anti-inflammatory properties of the endogenous gasotransmitter hydrogen sulfide (H₂S) were recently demonstrated in the context of different inflammatory diseases. In particular, H₂S is able to suppress the production of pro-inflammatory mediations by lymphocytes and innate immunity cells. Considering these biological effects of H₂S, a potential role in the treatment of inflammatory arthritis, such as rheumatoid arthritis (RA), can be postulated. However, despite the growing interest in H₂S, more evidence is needed to understand the pathophysiology and the potential of H₂S as a therapeutic agent. Within this review, we provide an overview on H₂S biological effects, on its role in immune-mediated inflammatory diseases, on H₂S releasing drugs, and on systems of tissue repair and regeneration that are currently under investigation for potential therapeutic applications in arthritic diseases.

Keywords: H2S-releasing biomaterials; arthritis; inflammation; non-steroidal anti-inflammatory drugs (NSAIDs); organosulfur compounds; oxidative stress; stem-cell therapy.

Figure 1

Schematic description of the effects of H₂S. The anti-inflammatory effect of H₂S is due to its ability to inhibit some essential pro-inflammatory transcription factors and intracellular signaling, such as nuclear factor κB (NF-κB) and phosphodiesterases (PDEs), and to improve angiogenesis through K_ATP channel/mitogen-activated protein kinase (MAPK) pathway activation. It inhibits the production of inflammatory cytokines and avoids the adhesion of leukocytes and endothelial cells. Moreover, the gasotransmitter can have pro- or anti-apoptotic effects depending on the cell type and its concentration. At the appropriate concentration, it is also able to have an anti-apoptotic effect due to its antioxidant properties, as well as its ability to increase the mitochondrial activity and the expression of anti-apoptotic proteins [17]. However, exogenous H₂S is also able to induce apoptosis in cancer cells. H₂S can also act on the vascular smooth muscle producing vasodilation. M1, macrophages M1; M2, macrophages M2; K_ATP, ATP-dependent K -channels.

Figure 2

Pathogenesis of inflammatory arthritides. Self-reactive T helper cells seem involved in the maintenance of inflammation, further sustained by B cells, especially in rheumatoid arthritis (RA), where it is possible to detect autoantibodies (), such as the rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Furthermore, innate immunity is involved in chronic inflammation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of the macrophages. Monocytes and macrophages, as well as dendritic cells, seem to play a vital role in the pathogenesis of inflammatory arthritis, as antigen-presenting cells (APCs), and they can express several pro-inflammatory cytokines. In early stages of inflammation, hypoxia and the production of ROS (reactive oxygen species) and RNS (reactive nitrogen species) seems to play a role in the initiation of the inflammatory process and induction of angiogenesis. The new blood vessels further maximize the recruitment of immune cells, amplifying the inflammatory process. The chronic inflammation finally perpetuates the production of pro-inflammatory cytokines (such as tumor necrosis factor-α (TNF-α)) and other mediators, such as prostaglandin E2, which ultimately generate vasodilation, infiltration of immune cells, and destruction of the cartilage. , dendritic cell/APC; , osteoclast; , chondrocyte.

Figure 3

Biological anti-inflammatory effects of H₂S. H₂S exerts an anti-inflammatory effect via different biologic effects: direct and indirect reducing action (Nrf2, ARE activation), a regulatory effect on the immune system via NF-kB interaction, interference with rolling and migration of circulating cells, inhibition of enzymes involved in the inflammatory signaling (protein tyrosine phosphatases (PTPs), PDEs). H₂S induces separation between Nrf2 and Keap1, allowing Nrf2 to enter the nucleus and bind to the ARE gene; furthermore, it modulates in a dose-dependent manner the expression of many cytokine genes, while it obtains an anti-apoptotic effect through Akt activation. H₂S, through action on ATP-sensitive potassium channels (K_ATP), inhibits the expression of adhesion molecules on the leukocytes (cluster of differentiation (CD)11/CD18) and endothelium (P-selectin, intracellular adhesion molecule 1 (ICAM1)).

Figure 4

Molecular structures of slow H₂S-releasing agents with potential anti-inflammatory properties for the treatment of arthritis. ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) and ATB-429 ([4-(5-sulfanylidenedithiol-3-yl) phenyl] 5-amino-2-hydroxybenzoate) are H₂S-releasing derivatives of mesalamine. ATB-337, ATB- 343, and ATB-345 are respectively diclofenac, indomethacin, and naproxen linked to a hydrogen sulfide-releasing moiety. ATB-346 is naproxen covalently linked to 4-hydroxythiobenzamide (TBZ). ACS-14 is aspirin linked to H₂S donors, ACS-21 is deacetylated aspirin linked to H₂S donors, and NBS1120 is a NO H₂S-releasing derivative of aspirin. GYY4137—morpholin-4-ium 4 methoxyphenyl phosphinodithioate; DAS—diallyl sulfide.