Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses

Abstract

Hydrogen sulfide (H₂S) is a biologically relevant signaling molecule in mammals. Along with the volatile substances nitric oxide (NO) and carbon monoxide (CO), H₂S is defined as a gasotransmitter. It plays a physiological role in a variety of functions, including synaptic transmission, vascular tone, angiogenesis, inflammation, and cellular signaling. The generation of H₂S is catalyzed by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). The expression of CBS and CSE is tissue specific, with CBS being expressed predominantly in the brain, and CSE in peripheral tissues, including lungs. CSE expression and activity are developmentally regulated, and recent studies suggest that CSE plays an important role in lung alveolarization during fetal development. In the respiratory tract, endogenous H₂S has been shown to participate in the regulation of important functions such as airway tone, pulmonary circulation, cell proliferation or apoptosis, fibrosis, oxidative stress, and inflammation. In the past few years, changes in the generation of H₂S have been linked to the pathogenesis of a variety of acute and chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary disease. Recently, our laboratory made the critical discovery that cellular H₂S exerts broad-spectrum antiviral activity both in vitro and in vivo, in addition to independent antiinflammatory activity. These findings have important implications for the development of novel therapeutic strategies for viral respiratory infections, as well as other inflammatory lung diseases, especially in light of recent significant efforts to generate controlled-release H₂S donors for clinical therapeutic applications.

Keywords: H2S donors; antiviral; hydrogen sulfide.

Figure 1.

Intracellular synthesis and degradation of H₂S. H₂S is produced by cytoplasmic and mitochondrial enzymes (cystathionine γ-lyase [CSE], cystathionine β-synthase [CBS], 3-mercaptopyruvate sulfurtransferase [3-MST], and cysteine aminotransferase [CAT]) using cysteine or homocysteine as substrates. Intracellular nontoxic H₂S levels are actively maintained by oxidation in the mitochondria by the enzyme sulfide quinone reductase (SQR), or methylation in the cytoplasm by thiol-S-methyltransferase (TMST). Free H₂S can also be bound by methemoglobin and by molecules with metal- or disulfide bonds and excreted with biological fluids.

Figure 2.

Role of H₂S in the physiopathology of the airways. Under physiological conditions, H₂S participates in regulating respiratory rhythm in the central nervous system and transporting electrolytes, and is necessary for normal development of lung vasculature and alveolarization. In various disease conditions, H₂S has been shown to inhibit inflammatory responses, pulmonary fibrosis, and oxidative stress, and to possess broad antiviral activity.