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Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

ABSTRACT: BACKGROUND:Lethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related. METHODS:At 6 h before and the start of 24 h anthrax PGN infusions, rats (n?=?198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 ?g/kg), non-selective and selective anti-inflammatory agents, respectively. RESULTS:Compared to controls, hydrocortisone 125 and 12.5 mg/kg each decreased 7-day lethality (p???0.004). Hydrocortisone 125 mg/kg decreased IL-1?, IL-6, TNF?, MCP, MIP-1?, MIP-2, RANTES and nitric oxide (NO) blood levels at 4 and 24 h after starting PGN (except MCP at 24 h). Each decrease was significant at 4 h (except MIP-1? that was significant at 24 h) (p???0.05). Similarly, hydrocortisone 12.5 mg/kg decreased each measure at 4, 24 and 48 h (except TNF? at 24 h and MIP-1? at 24 and 48 h and NO at 48 h). Decreases were significant for IL-6 and NO at 4 h and RANTES at 48 h (p???0.05). Hydrocortisone 1.25 mg/kg had non-significant effects. Each TNFsr dose decreased lethality but non-significantly. However, when doses were analyzed together, TNFsr decreased lethality in a potential trend (p?=?0.16) and IL-6 and NO significantly at 4 h (p?=?0.05). CONCLUSIONS:Peptidoglycan-stimulated host inflammation may contribute to B. anthracis lethality.

SUBMITTER: Li Y

PROVIDER: S-EPMC7674536 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

Li Yan Y Cui Xizhong X Shiloach Joseph J Wang Jeffrey J Suffredini Dante A DA Xu Wanying W Liu Wancang W Fitz Yvonne Y Sun Junfeng J Eichacker Peter Q PQ

Intensive care medicine experimental 20201118 1

<h4>Background</h4>Lethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related.<h4>Methods</h4>At 6 h before and the start of 24 h anthrax PGN infusions, rats (n = 198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 μg/kg), non-selective and selective ant ...[more]

PMID: 33206255

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Project description:Nitric oxide (NO) is a key physiological regulator in eukaryotic and prokaryotic organisms. It can cause a variety of biological effects by reacting with its targets or/and indirectly inducing oxidative stress. NO can also be produced by bacteria including the pathogenic Bacillus anthracis; however, its role in the infectious process only begins to emerge. NO incapacitates macrophages by S-nitrosylating the intracellular proteins and protects B. anthracis from oxidative stress. It is also implicated in the formation of toxic peroxynitrite. In this study we further assessed the effects of B. anthracis NO produced by the NO synthase (bNOS) on bacterial metabolism and host cells in experiments with the bNOS knockout Sterne strain. The mutation abrogated accumulation of nitrite and nitrate as tracer products of NO in the culture medium and markedly attenuated growth in both aerobic and microaerobic conditions. The regulatory role of NO was also suggested by the abnormally high rate of nitrate denitrification by the mutant in the presence of oxygen. Anaerobic regulation mediated by NO was reflected in reduced fermentation of glucose by the mutant correlating with the reduced toxicity of bacteria toward host cells in culture. The toxic effect of NO required permeabilization of the target cells as well as the activity of fermentation-derived metabolite in the conditions of reduced pH. The host cells demonstrated increased phosphorylation of major survivor protein kinase AKT correlating with reduced toxicity of the mutant in comparison with Sterne. Our global proteomic analysis of lymph from the lymph nodes of infected mice harboring bacteria revealed numerous changes in the pattern and levels of proteins associated with the activity of bNOS influencing key cell physiological processes relevant to energy metabolism, growth, signal transduction, stress response, septic shock, and homeostasis. This is the first in vivo observation of the bacterial NO effect on the lymphatic system.

Project description:Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung condition. It is characterized by disruption of gas exchange inside the alveoli, accumulation of protein edema, and an increase in lung stiffness. One major cause of ARDS is a lung infection, such as SARS-COV-2 infection. Lungs of ARDS patients need to be mechanically ventilated for airway reopening. Consequently, ventilation might damage delicate lung tissue leading to excess edema, known as ventilator-induced lung injury (VILI). Mortality of COVID-19 patients under VILI seems to be higher than non-COVID patients, necessitating effective preventative therapies. VILI occurs when small air bubbles form in the alveoli, injuring epithelial cells (EPC) due to shear stress. Nitric oxide (NO) inhalation was suggested as a therapy for ARDS, however, it was shown that it is not effective because of the extremely short half-life of NO. In this study, NO-releasing nanoparticles were produced and tested in an in vitro model, representing airways in the deep lung. Cellular injuries were quantified via fluorescent live/dead assay. Atomic force microscopy (AFM) was used to assess cell morphology. qRT-PCR was performed to assess the expression of inflammatory markers, specifically IL6 and CCL2. ELISA was performed to assess IL6 and confirm qRT-PCR results at the protein level. Finally, ROS levels were assessed in all groups. Here, we show that NO delivery via nanoparticles enhanced EPC survival and recovery, AFM measurements revealed that NO exposure affect cell morphology, while qRT-PCR demonstrated a significant downregulation in IL6 and CCL2 expression when treating the cells to NO both before and after shear exposure. ELISA results for IL6 confirmed qRT-PCR data. ROS experiment results support our findings from previous experiments. These findings demonstrate that NO-releasing nanoparticles can be used as an effective delivery approach of NO to deep lung to prevent/reduce ARDS associated inflammation and cell injuries. This information is particularly useful to treat severe ARDS due to COVID-19 infection. These nanoparticles will be useful when clinically administrated to COVID-19 patients to reduce the symptoms originating from lung distress.

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Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

Publications

Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

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