factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. .... Ald resulting in limitation cytokines storm associated with MERS-CoV infection ...
Preventing Morbidity and mortality Of ICU Patients caused by MERS-CoV By Using Angiotensin 2 And Aldosterone Blockers with Glutathione Antioxidant
1-Introduction Epidemiologic data, supported by clinical manifestations, strongly propose that cytokine over activity of immune responses may underlie most ICU patient’s death of MERS-CoV infection. The high significant level Cytokines IL-1β, IL-6 and IL-8 were induced by MERSCoV at 30 hours of infection [13]. MERS-CoV causes severe pulmonary disease in human beings with the same pattern of SARS infection despite different receptor. Recently, dipeptidyl peptidase 4 (DPP4), also known as CD26 is identified as the cellular receptor for MERS-CoV. MERS-CoV spike protein initiates infection by attaching the virus to CD26 of host cells [14]. Existing of DPP-4 also on lymphocyte cell surface protein plays an important role in T cell immunity. The imbalance between pathogenic and regulatory T cells initiates a T cell mediated disease [27]. Angiotensin II is considered as a stimulator of variety cell mediated factors such as growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. Angiotensin II and tumor necrosis factor alpha TNF-a have a crosstalk effect [26]. Alongside, Angiotensin II stimulates NF-kB in neutrophils, monocyte, and macrophages. NF-kB is involved in immunocyte proliferation, maturation, and activation. [19] In the pulmonary capillary, high production of local angiotensin II causes the vessel to constrict. Angiotensin II regulates the balance between vasoconstriction, and downstream of vasoconstrictors that is essential to function alveolus. On the other hand, Angiotensin II through its type 1 receptors mediates apoptosis of endothelial cells and type II pneumocytes. [17] Aldosterone increases ACE activity by up-regulating angiotensin receptors in the tissues. In addition, crosstalk between Angiotensin II and Aldosterone synergistically increases the cell responses to the inflammatory mediators. Immune cells use NADPH oxidase to produce (ROS), and then H2O2 to combat infection. ACE metabolites of bradykinin, angiotensin, and neuropeptides play a major role in inflammatory airway diseases. [16] According to Drosten, MERS-CoV causes the same pattern of SARS-CoV disease even though it does not require the same receptor. Lau et al. demonstrates that the early and late proinflammatory cytokines are induced by MERS-CoV. Eight cytokine genes and proteins such as TNF-α, IL-1β, IL-6, IL-8, IFN-β, monocyte chemotactic protein-1, transforming growth factor-β and IFN-γ-induced protein (IP)-10 were investigated in Lau et al., study. Among 8 Cytokines IL-1β, IL-6 and IL-8 which were induced by MERS-CoV were significantly high at 30 h of infection [13] MERS-CoV infection causes a suffered dramatic health issues lead to death. Cytokine storm is due to an imbalance of immune responses feedback loop, which results in severe pulmonary, severe loss of lymphocytes, monocytes, renal failure and coagulation in the vasculature. [6] · What is the Clinical significance of these Cytokines IL-1β, IL-6 and IL-8?
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Interleukin-1 beta IL-1β Increased production of IL-1B is errors in the innate immune system, causes a number of different auto inflammatory syndromes without of producing of autoantibodies or antigenspecific T or B cells. [15] These syndromes are diverse, but in general are fever, joint pains, skin rashes, and abdominal pains. [22] Interleukin 6 IL-6 IL-6 is a main mediator of the acute phase response secreted by macrophages in response to specific microbial molecules such as fever. It stimulates the inflammatory and autoimmune processes in many diseases. [3] Both upstream and downstream IL-6 signalling in macrophages, is dependent upon activation of the NFκB signalling pathway, while its expression in intramuscular is regulated by signalling cascades, involving the Ca2+/NFAT and glycogen/p38 MAPK pathways. [5] Interleukin 8 (IL-8) Interleukin IL-8 is produced by variety of cell types such as epithelial cells, airway smooth muscle cells, and endothelial cells as will as macrophages. [10] It induces chemotaxis in target cells to attract neutrophils and also other granulocytes to the site of infection. In target cells, IL-8 produces a sequence of physiological reactions such as increases in intracellular Ca2+, exocytosis, which are essential for migration and phagocytosis, for example, histamine release, and the oxidative burst (ROS). [24] IL-8 is considered as a key role in the pathogenesis of bronchiolitis in a viral infection. [25] Interestingly, Ang II stimulates mononuclear leukocyte to be a generate and release of the CXC chemokine IL-8 and various CC chemokines. [20] Furthermore, Angiotensin II induces transduction signaling and responses in the immune cells result in producing of reactive oxygen species (ROS) To fight infections. Immune cells use NADPH oxidase to produce (ROS), and then H2O2. Neutrophils and monocytes utilize a peroxidase enzyme; myeloperoxidase to produce hypochlorite, to destroy microbes [11]. Glutathione peroxidase/ reductase is an antioxidant enzyme that plays a critical role in the protection of the cellular reductive potential [7]. Glutathione peroxidase/ reductase ratio is as a consequence of a combination of the removal rates of H2O2 by GSH peroxidase and GSSG reduction by GSH reductase [21]. Thus, the ratio of glutathione disulfide (GSSG)/2 glutathione (GSH) is considered as a significant indicator of the cellular redox state [21]. Thereby, neutralizing ROS by the GSH-peroxidase-coupled reaction, will block the pathway to cytokine augmentation [9]. Therefore, the ratio between them can be regulated by the GSH concentration. Commonly, in the complementary and alternative medicine community, numbers of pulmonary disease are treated by Inhaled glutathione such as asthma, chronic obstructive pulmonary disease, bronchitis, sinusitis, and chemical sensitivity [2]. 2005 pilot study of the effect of inhaled buffered reduced GSH indicates the promise on the Clinical status of Patients With Cystic Fibrosis [4]. Recently, studies demonstrated that the gene polymorphism Angiotensin II type 1 receptor has associated with different risk factor for ACS incidence, and septic shock. This variation in polymorphism is associated with a greater severity and risk of sudden death because of acute coronary syndrome ACS or septic shock [12] [18]. ACE and TNF-a genotype may play a role in the modulation of proinflammatory cytokine production. [8] It is possibly that the ACE genotype is linked to symptomatic/ asymptomatic MERS-CoV infection. A recent study suggested that the combination of aldosterone blockade with RAS inhibitors be more effective in the reduction of renal production of profibrotic cytokines such as TGFβ1and PAI-1 diabetes. The combined treatment was associated with a prevention renal damage than either therapy alone. Taken together, these results indicate that blockade of the
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aldosterone system based on RAS inhibition may be a new therapeutic strategy for retarding the progression of diabetic nephropathy. [1] In a primary study, ATB showed acceleration relieve from West Nile virus, encephalitis. According to Moskowitz and Johnson,"it may be equally useful in SARS” “as well as most other viruses." Hyperactivity of ACE is associated with a variety of autoimmune system disorders such as rheumatoid arthritis, lupus, and fibromyalgia/chronic fatigue syndrome. Moskowitz and Johnson have got satisfying clinical responses to ARBs in patients with T-cell disorders such as psoriasis and alopecia areata, together with viral diseases. [17] Hypothesis: Accordingly, it may be there is a chance to save lives of ICU patients by using Angiotensin II type 1 receptor and Aldosterone blockers with Glutathione antioxidant. Combination of these drugs will inhibit the synergistic effect of crosstalk between Ang II and Ald resulting in limitation cytokines storm associated with MERS-CoV infection. Additionally, Glutathione antioxidant plays a critical role in maintaining the cellular reductive potential state that will reduce the ROS, the main activator of cytokine's propagation. Additionally, Glutathione may prompt alveoli function by saving equilibrium between free cysteine sulfhydryl groups of ACE and oxidized cystine bridges. 2-Method: • We will modify the design and setup all details After approval. • Under supervision in ICU select control and sample number of patients with MERSCoV admitted after 30 Hours of infection. Measure all cytokines and Angiotensin II level in serum of the patient in sample and control groups. • Measure the serum superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S-transferase (GST) activities using appropriate methods and compared with healthy controls and before/after treatment. • Patients will be given Valsartan (IV) in an ascending manner concentration 5, 10 and 20 mg/day to assess the tolerability and basic pharmacokinetics of the (IV) formulation combined with Eplerenone 50mg/day or Spironolactone 25/day mg. Blood pressure, renal function, and electrolytes; Plasma potassium concentration should be monitored frequently. • Oral/ inhaled glutathione 66–148 mg/kg/day in divided doses to evaluate and adjust proper dose [23], [4] • Use statistical tests and Risk factors to analyze. • Data will be collected from administrative, pharmaceutical, and laboratory. • Computerized databases by means of a relational database management system. • Make Cytokine secretion assays, and cytokine detection. (Before and after) 3-Data analysis What the scores/ data will be used? What tests used for analysis? What is the expected pattern of result correlation? 4-Discussion: Restate expected outcome (hypothesis) What would limit the conclusions that could be drawn? If results were consistent with expectation 5-Potential implications of using AT2B and Aldosterone -The most interesting finding can be the detected of a cytokine storm. -The examination of multiple methods of control could help in the treatment. - Target any possible negative outcomes and uncover unknown mechanisms that may be of clinical relevance.
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