The Effects of H2S and Recombinant Human Hsp70 on Inflammation Induced by SARS and Other Agents In Vitro and In Vivo

Abstract

The ongoing epidemic caused by SARS-CoV-2 infection led to the search for fundamentally new ways and means to combat inflammation and other pathologies caused by this virus. Using a cellular model of lipopolysaccharide (LPS)-induced sepsis (human promonocytes), we showed that both a hydrogen sulfide donor (sodium thiosulfate, STS) and a recombinant Heat shock protein 70 (rHsp70) effectively block all major inflammatory mediators when administrated before and after LPS challenge. The protective anti-inflammatory effect of rHsp70 and H2S was also confirmed in vivo using various animal models of pneumonia. Specifically, it was found that rHsp70 injections prevented the development of the acute respiratory distress syndrome in highly pathogenic pneumonia in mice, increased animal survival, and reduced the number of Programmed death-1 (PD-1)-positive T-lymphocytes in peripheral blood. Based on our model experiments we developed a combined two-phase therapeutic approach for the treatment of COVID-19 patients. This procedure includes the inhalation of hot helium–oxygen mixtures for induction of endogenous Hsp70 in the first phase and STS inhalation in the second phase. The use of this approach has yielded positive results in COVID-19 patients, reducing the area of lung lesions, restoring parameters of innate immunity and T-cell immune response against coronavirus infection, and preventing the development of pulmonary fibrosis and immune exhaustion syndrome.

The Role of Hsp70 in Adaptation to Adverse Conditions and Its Possible Medical Application

“…Interestingly, in our experiments administration of recHsp70 significantly reduced LPS-induced TLR4 expression in human macrophage cells (THP1) [181]. The ability to eliminate damaged proteins and prevent the formation of aggregates of different nature is obviously the most important protective function of Hsp70 described for such diseases as AD, Parkinsonism, ALS, and many others.…”

“…Along these lines, in our experiments on a small sample of Covid patients [181], we have recently demonstrated that hot helium inhalation inducing Hsp70 followed by inhalation of hydrogen sulfide donor has a pronounced therapeutic effect preventing lung fibrosis in the patients. Moreover, in our in vitro and in vivo experiments we showed that different hydrogen sulfide donors as well as recHsp70 significantly reduced the level of proinflammatory cytokines, ROS, and other consequences of LPS-induced inflammation [181].…”

“…Along these lines, in our experiments on a small sample of Covid patients [181], we have recently demonstrated that hot helium inhalation inducing Hsp70 followed by inhalation of hydrogen sulfide donor has a pronounced therapeutic effect preventing lung fibrosis in the patients. Moreover, in our in vitro and in vivo experiments we showed that different hydrogen sulfide donors as well as recHsp70 significantly reduced the level of proinflammatory cytokines, ROS, and other consequences of LPS-induced inflammation [181]. The contradictory and difficult-to-explain results sometimes obtained when analyzing the action of endogenous and recHsp70 may be related to the fact that different members of this family are preferentially synthesized in different organs and tissues and to the numerous tissuespecific posttranslational modifications to which members of the Hsp70 family are often subjected [180,196].…”

“…In a model of infectious lung inflammation, it was shown that intraperitoneal injection of recHsp70 reduced the number of programmed death-1 (PD-1) positive Tlymphocytes in peripheral blood by several times and improved other important lung characteristics such as lung coefficient (Fig. 4) [181].…”

The Protective Action of Hsp70 and Hydrogen Sulfide Donors in THP-1 Macrophages in the Lipopolysaccharide-Induced Inflammatory Response by Modulating Endocytosis

“…Suppression of endogenous enzymes involved in the formation of H 2 S in various diseases, or genetic defects in enzymatic systems of H 2 S biosynthesis lead to the development of various pathologies, including oncological, cardiovascular, neurodegenerative, autoimmune (rheumatoid arthritis, and asthma) pathologies [15][16][17][18]. In recent years, our studies of the protective properties of recombinant human Hsp70 and various H 2 S donors showed that these compounds protect cells from the action of LPS [6,11,19,20]. It is also known that elevated levels of H 2 S in cells can lead to the induction of Hsp70 formation [21].…”