How does glutathione inhibit oxidative stress?

 Glutathione (GSH) is a small tripeptide consisting of glutamic acid, cysteine and glycine, with a molecular weight of 307.3 [1] (Fig. 1).It was discovered in 1921 by Fred- erick G, Hopkins, Nobel Prize winner and President of the Royal Society.

 

Glutathione is a naturally occurring endogenous substance in the body, which is widely distributed in human liver, spleen, kidney, lungs and other organs and tissues and cells (Fig. 2). The main feature of GSH is that it has free sulfhydryl groups, so it has a strong ability to donate electrons or proton hydrogens to participate in redox processes in vivo, and it constitutes an antioxidant system of the body, scavenging all kinds of peroxide and free radicals.2 The structural characteristics of GSH have determined its important physiological functions in organisms by regulating cell proliferation and gene expression rates[3] . The structural characteristics of GSH determine that it can play important physiological functions in organisms by regulating cell proliferation and gene expression rate[3] , and therefore it has been widely utilized as a drug in clinical medicine and other related fields[4-7] .

 

Examples include viral liver injury, chemical liver injury, kidney injury, various forms of hypoxemia, and severe respiratory distress syndrome.

This paper analyzes the mechanism by which glutathione is involved in the regulation of the human immune system, not only by strengthening immunity, but also by suppressing oxidative stress and inflammation, thereby suppressing the resulting over-immune response. One of the main reasons for the deaths of the severely ill patients in this case was the storm of immune factors brought about by COVID-19 infection of alveolar cells and hepatocytes, resulting in complications such as hypoxemia and respiratory distress syndrome. This article also presents hypotheses and inferences about the potential of glutathione for the treatment of neocoronaryngitis.

 

1 Inhibition of oxidative stress by glutathione and effects on the immune system

1.1 Role of glutathione on the immune system

The immune system is the body's first line of defense against all viral infections and health threats. The immune system is a complex system that automatically screens, detects and attacks harmful microorganisms, allergens, cancer cells, transplanted tissues, etc., primarily through lymphocytes, which are small but structurally specialized to eliminate pathogens through specific immune responses. Lymphocytes are small but highly structured and can eliminate pathogens through specific immune responses. B lymphocytes screen and label pathogens; labeled pathogens become targets for T lymphocytes. Helper T cells induce immune cells to join the fight, killer T cells destroy these pathogens, and suppressor T cells induce a cessation of the immune response when the pathogen has been completely eliminated.

 

When lymphocytes attack pathogens, they release highly oxidizing chemicals, such as peroxides, which are neutralized by GSH to protect the lymphocytes from damage. At the same time, lymphocytes are constantly replicating themselves, absorbing oxygen and producing oxidants to defend themselves against a wide range of pathogens. In this process, more GSH is needed to neutralize the oxidants produced, increasing the resistance of the lymphocytes and protecting their health. In summary, there are two ways in which the immune system consumes GSH in the process of destroying pathogens, one of which requires GSH to neutralize free radicals and the other requires GSH to promote the growth of immune cells.

 

In a similar study, it was found that elevated levels of GSH increased the ability of the immune system to fight off such infections. Dr. Bounous[8] and his team at McGill University conducted a study to observe the effects of feeding ABD-activated factors enriched with GSH precursors on the immunity of experimental animals. It was found that the animals had increased intracellular levels of GSH and increased immune responses to foreign substances. Interestingly, the same results were not found in the casein-enriched control group. The protective effect of GSH on the immune system was found to be twofold: it enhances the activity of immune cells and acts as an intracellular antioxidant.

 

The immune system defends itself against infections and other health threats through a variety of cells, the healthy growth and activity of which depends on GSH levels. Glutathione (GSH) is at the heart of all immune functions, and raising and maintaining GSH levels can minimize the damage caused by these diseases.

 

1.2 Improvement of the body's antioxidant capacity

The human body produces a large number of free radicals every day, and environmental factors also promote the generation of free radicals in the human body. Free radicals have a strong oxidizing ability. An appropriate amount of free radicals is the body's defender, which can kill bacteria, viruses and decompose poisons; however, excessive free radicals will oxidize normal substances in the human body, destroy the cellular structure, and promote cellular malignancy.

 

Although the etiology of respiratory diseases such as asthma, pneumonia, and bronchitis is complex, the continuous inflammatory response and oxidative stress caused by the damage of free radicals and other reactive oxygen species to tissues and cells are the main pathogenic mechanisms of respiratory diseases[9-11] . Glutathione, as an antioxidant, can quickly and effectively remove free radicals from the body because it contains sulfhydryl groups (-SH), which are susceptible to oxidation. Therefore, in the human immune system, glutathione can protect the sulfhydryl groups in proteins and enzymes from being oxidized by free radicals and other harmful substances through its own oxygenation, so that they can better perform their physiological functions.

 

An excess of oxidants or a decrease in antioxidants can lead to an oxidative/antioxidant imbalance in the body. Oxidative stress can directly damage biological macromolecules, causing the release of inflammatory factor gene expression and synthesis resulting in inflammatory damage leading to apoptosis. With the publication of the first study on oxidative stress in pulmonary fibrosis by Cantin [12] in 1987, more and more scholars have begun to explore the pathogenesis of oxidative damage in pulmonary fibrosis. Studies have shown that correcting the oxidative/antioxidative imbalance and increasing GSH levels in blood and lung tissue can reduce the degree of pulmonary fibrosis caused by oxidative injury.

 

Under the action of some damaging factors, the human body will be induced to generate a large number of free radicals accumulation, and when the cellular antioxidant protection mechanism is insufficient, it will also cause the accumulation of reactive oxygen species and toxicity to the cells, thus forming an imbalance between oxidative and antioxidant, which is known as oxidative stress in medicine. The drug atomolan (the main component of which is reduced glutathione (GSH)) has the function of antioxidant and free radical neutralization, and can inhibit peroxidative damage[13] . It has also been shown that oxidative metabolism in organisms generates a small amount of free radicals, which the body's antioxidant system needs to neutralize in order to maintain the metabolic balance of free radicals. Glutathione peroxidase (GPX) is one of the most important antioxidant enzymes in biological organisms, which can eliminate hydrogen peroxide and lipid peroxides and block the further damage caused by reactive oxygen radicals, and it is an important scavenger of reactive oxygen radicals in biological organisms [14].

 

Therefore, glutathione, as the most abundant and important substance in the antioxidant system that naturally exists in human cells, deserves to be the main force in scavenging free radicals in the human body, and is a "super antioxidant" [15].

 

1.3 Mechanisms that regulate the inflammatory response

Inflammation is the body's defense response to damage caused by bacteria, viruses, chemical factors, and necrotic tissues. Inflammatory factors can regulate the onset and development of the inflammatory response as well as the repair of damaged tissues [16]. The regulation of inflammatory factor expression is a key step in the regulation of the inflammatory response [17]. The dysregulation of inflammatory factor expression is closely related to allergies, chronic inflammation, autoimmune diseases, and cancer [18-19].

 

Nitric oxide (NO) synthesis plays an important role in the regulation of inflammatory factors. The use of NO to modulate the expression of inflammatory factors has been widely used to regulate the course of inflammatory responses [20-22]. S- nitrosoglutathione reductase (GSNOR) is a key protein in the metabolic regulation of the NO signaling pathway in vivo [23], and the NO signaling pathway is dually regulated by NOS (nitric oxide synthase NOS) and GSNOR, which synthesizes NO and enhances NO signaling in vivo, while GSNOR metabolizes nitrosoglutathione in vivo. NOS synthesizes NO and enhances NO signaling in the body, while GSNOR metabolizes nitrosoglutathione (GSNO) and down-regulates NO signaling[24-25] . Excessive lowering of GSNOR will disrupt the internal balance of NO, leading to the dysregulation of NO signaling in many tissues and organs such as the heart, blood vessels, respiratory tract, and the liver, and affecting the normal functioning of the organism[26-29] . Therefore, GSNOR is considered to be a new important inflammation-regulating molecule, which can promote inflammation by lowering the level of GSNOR and inhibit excessive inflammation by up-regulating the level of GSNOR in clinical medicine. In this regard, intracellular levels of reduced glutathione again play an important role in the regulation of inflammation.

 

Macrophages in the human immune system also enhance the immune-inflammatory response through the up-regulation of iNOS (inducible nitric oxide synthase) and the down-regulation of GSNOR [30], and vice versa, they reduce the excessive inflammatory response so as not to damage the immune cells as well as normal tissues, and to reduce the occurrence of chronic inflammation and other diseases related to the immune system.

 

1.4 Treatment of autoimmune diseases

Under normal conditions, an effective antioxidant defense system exists in the body to maintain a dynamic balance between free radical production and scavenging. When free radicals are overproduced or the collective antioxidant defense system is impaired, the body will be in a state of oxidative stress, leading to tissue cell damage [31].

Wang Zhongchen et al. concluded that GSH has an important effect on liver fibrosis and immune function in patients with chronic hepatitis B (CHB), which is a tripeptide containing sulfhydryl groups that activates the biological redox system and scavenges free radicals, and can effectively improve the hepatic impairment of patients with CHB with a better effect on anti-hepatic fibrosis [32]. It can effectively improve the liver function damage of CHB patients and has a better antihepatic fibrosis effect, so it can effectively improve the immune function and quality of life of patients [32].

 

Numerous studies have shown that excessive reactive oxygen species (ROS) are closely related to the onset and progression of Parkinson's disease (PD), which is a disease in which the body is subject to long-term oxidative stress, and therefore the removal of the toxic effects of ROS in the brain is an important way of treating the disease. The antioxidant glutathione plays a crucial role in this process, and increasing the concentration of glutathione in the brain or applying glutathione analogs and precursors to prevent and treat PD and other neurodegenerative diseases has become an important target in current drug development [33].

 

Meanwhile, the glutathione redox system, which includes reduced glutathione, oxidized glutathione (GSSG), glutathione oxidase and glutathione reductase, is known as the tissue antioxidant system because of its ability to fight against oxygen radicals and to protect lung tissues from oxidative damage. Recent studies have shown that a decrease in the function of this system or an increase in the production of oxygen free radicals can lead to a series of harmful oxygenation reactions in the body. Therefore, research on the relationship between glutathione and respiratory diseases has received more and more attention, and progress has been made continuously. Ho Kwun Ying also believes that glutathione has a significant relationship with respiratory diseases [36].

 

By measuring the serum levels of total antioxidant capacity (T-AOC), malondialdehyde (MDA), reduced glutathione (GSH), and glutamine (GLN) in patients with systemic lupus erythematosus (SLE), it was analyzed that the level of oxidation in patients with SLE is significantly higher and the antioxidant capacity is significantly lower. It was found [34] that the serum GSH content of SLE patients was not statistically different from that of normal control group. In contrast, the GLN content was significantly lower than that of normal control group, indicating that GLN provides raw materials for synthesizing and replenishing GSH consumed in the peroxidized state. Therefore timely supplementation of exogenous GLN and GSH can enhance the antioxidant capacity of the organism [35].

 

2 Other effects of glutathione on the human body

Glutathione is an important antioxidant in the human body, scavenging free radicals, enhancing the activity of antioxidant enzymes, and improving the body's antioxidant defense. The effect of glutathione is very obvious in acute infections, such as acute pneumonia; in chronic infections, such as hepatitis or AIDS, the depletion of GSH is more obvious. Therefore, glutathione has been widely used as an adjuvant drug in treating various diseases.

 

2.1 Effective reduction of ventilator mechanical ventilation time

Improper use of ventilators can cause lung injury, resulting in extensive alveolar-capillary membrane damage, alveolar inflammatory infiltrates, and a series of lung injury changes accompanied by the release of inflammatory factors[37] . Studies have shown[39] that reduced glutathione, due to its anti-inflammatory and antioxidant effects, can inhibit the phosphorylation of IkB (human nuclear factor inhibitory protein), thereby reducing the activation of NF-kB (nuclear transcription factor), controlling gene transcription, and inhibiting the synthesis of the related cytokines, IL-6 (interleukin 6), IL-8, and TNF-α (tumor necrosis factor). At the same time, by affecting the expression of IL-2 receptor, it reduces its binding to effector cells, and promotes the internalization and degradation of lL-2, IL-6 and IL-8 (interleukin 2/6/8) in effector cells, thus reducing the activation of effector cells. It can shorten the duration of mechanical ventilation, hospitalization and ICU stay, reduce the aggregation of effector cells such as granulocytes and monocytes and their adhesion to the target cells, protect the target cells and prolong the survival time of patients.

 

2.2 Anti-aging and disease prevention

Newly published medical research reports that glutathione helps promote the health of the adaptive immune system, making it important to increase glutathione levels to maintain health and prevent disease. Below are the results of the research on the effects of glutathione on the immune system:

Dr. Bauerch of the Indiana University School of Medicine points out that glutathione supplements can remove toxic substances from the body, restore the normal functioning of organs and slow down the aging process, and there is no better way to strengthen the immune system.

Dr. Woolf [38]: "The German Cancer Research Center has concluded from several studies that glutathione supplementation is an effective product for improving immune system function. It can overcome the cellular deficiencies that are common in middle-aged and older adults, which significantly affect the cellular health of the immune system and lead to increased infections and morbidity. Therefore, older people are more likely to benefit from glutathione supplementation. Regular supplementation is also recommended for younger people."

 

Gutman [40] also concluded that although GSH deficiency is severe only in critically ill patients, healthy people taking GSH supplements can prevent disease and have a protective effect on their own health.

 

2.3 Anti-cancer effects

Guo et al. suggested that GST (glutathione transferase) is a detoxifying enzyme that facilitates the binding of GSH to foreign substances that enter the organism, including carcinogenic metabolites. These foreign substances include oncogenic metabolites, most of which may be derived from the oxidation of organismal xenobiotics to produce electrophilic carcinogens that react with macromolecules in the organism, such as proteins and DNA, etc. GSH binds to these carcinogens, which are finally excreted as thiol uric acid derivatives [41].

 

He et al. also recognized that GSH can block the production of new free radicals, although only indirectly by scavenging, when it inhibits the initiation of lipid peroxidation or terminates the development of lipid peroxidation through a number of enzyme systems. The molecular properties of GSH, the abundance of GSH and GST in the cells of various tissues, and the complete system of metabolic enzymes provide an important metabolic pathway for the detoxification of electrophilic substances with potential cytotoxic and genotoxic damages [42].

 

3 Inferences about the role of COVID-19

3.1 Principles of neocoronavirus lethality

Neocoronavirus first binds to ACE2 in the alveolar epithelial cells and begins to attack the lungs. As the disease progresses, the virus spreads and attacks other organs, such as the spleen, lymph nodes, liver, and intestines, and ultimately causes organ failure. The main causes of death are hypoxemia, respiratory distress syndrome, and its complications.

 

3.2 Early stage of neocoronary pneumonia and hypoxemia

Hypoxemia is a condition in which the blood does not contain enough oxygen and the partial pressure of oxygen (PaO2) in the arterial blood is lower than the lower limit of normal for a person of the same age, as evidenced by a decrease in the partial pressure of oxygen and the oxygen saturation of the blood. Hypoxemia often occurs as a result of low oxygen levels in inhaled air, insufficient alveolar gas, diffusion dysfunction, and circulatory dysfunction. The lining fluid of alveolar epithelial cells contains high levels of both glutathione peroxidase (GSH-Px, GPx) and GSH, and the reducing capacity of GSH-Px is dependent on the presence of high levels of GSH [43].

 

GSH-Px catalyzes the reaction between H2O2 and GSH when protonated by reduced coenzyme II (NADPH) to produce H2O and GSSH, which is then catalyzed by glutathione reductase through the glutathione cycle to produce GSH, ensuring that the amount of sulfhydryl groups in the cell is not reduced. The combination of sulfhydryl groups with free radicals in the body can directly reduce free radicals and convert them into easily metabolized acids, thus accelerating the excretion of free radicals. In patients with systemic or local hypoxemia caused by anemia, intoxication or tissue inflammation, it can reduce cell damage and promote repair[44] . Therefore, glutathione can be used in the clinical treatment of patients with hypoxemia and is one of the clinical indications for glutathione approved by the National Food and Drug Administration.

 

3.3 New Crown Pneumonia Critical Illness and Acute Respiratory Distress Syndrome

Among patients infected with COVID-19, those with severe disease may develop acute respiratory distress syndrome (ARDS) for a variety of reasons. ARDS is an acute, progressive hypoxic respiratory failure that occurs after severe infections, trauma, shock, and other intra- and extra-pulmonary attacks, and is characterized by alveolar capillary damage. ARDS is an acute, progressive hypoxic respiratory failure that occurs after severe infections, trauma, shock, or other attacks inside or outside the lungs, with alveolar capillary damage as the main manifestation, and it belongs to the serious stage of acute lung injury (ALI). It is characterized by respiratory tachycardia and distress, progressive hypoxemia, and diffuse alveolar infiltration on X-ray. Glutathione is effective in inhibiting autoimmune stress, thereby protecting cells from oxidative damage. It is therefore hypothesized that glutathione may inhibit respiratory distress syndrome and be used in the clinical management of patients with respiratory distress syndrome. Respiratory distress syndrome is also one of the clinical indications for glutathione approved by the National Food and Drug Administration.

 

3.4 Complications arising from new crowns

Lancet Respiratory Medicine published a study by a joint team from Huazhong University of Science and Technology and Wuhan Jingyintan Hospital. The study examined the clinical disease progression and outcomes of 52 critically ill patients with new crown pneumonia enrolled at Jinyintan Hospital. The results of the study showed that patients who were older (>65 years) and had a history of underlying disease and acute respiratory distress syndrome were at greater risk of death. Also, 54% of patients with CKP had varying degrees of liver damage. Glutathione has been shown to be effective in the treatment of liver disease, respiratory disease and other chronic conditions.

 

In conclusion, GSH, as an endogenous detoxifier, can effectively remove all kinds of harmful peroxides and excessive free radicals produced by hypoxemia and acute respiratory distress syndrome in human body, and thus inhibit the stress response of our own immune system. Moreover, as an old drug with new applications, we hope that glutathione can attract the attention of experts in various fields as soon as possible and pass the clinical trials as soon as possible, so as to win precious time for saving lives and play a role in epidemic prevention and control.

 

References:

[1] Xie Yaqing, Liang Xiaomei, Ye Weixia. Progress of pharmacological effects and clinical applications of reduced glutathione[J]. Chinese Pharmaceutical Industry, 2013, 22(7):124-127.

[2] Liu AH. Mechanism of action of reduced glutathione and its clinical application[J]. China Medical Guide, 2013, 09:391-393.

[3] Iles K , Liu R. Mechanisms of glutamate cysteine ligase (GCL) induction by 4 - hydroxynonenal. J Free Radic Biol Med , 2005, 38: 547-556.

[4] Dilokthornsakul , W.; Dhippayom , T.; Dilokthornsakul , P., The clinical effect of glutathione on skin color and other related skin conditions: a systematic review. journal of cosmetic dermatology, 2019, 18(3): 728-737.

[5] Klatt , P.; Lamas , S., Regulation of protein function by S- glutathiolation in response to oxidative and nitrosative stress. European journal of biochemistry, 2000, 267(16):4928-4944.

[6] Hayes, J. D.; McLellan, L. I. ,Glutathione and glutathione -dependent enzymes represent a co -ordinately regulated defense against oxidative stress. Free Radical Research Communications, 1999, 31(4):273-300.

[7] Lv , H., Zhen , C., Liu , J., et al. Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy. oxidative medicine and cellular longevity, 2019, 2019, 3150145.

[8] Bounous , G , Batist , G , Gold , P. Whey proteins in cancer prevention [J].  Cancer Letters , 1991, 57(2):91-94.

[9]Fitzpatrick A M , Jones D P , Brown L A. Glutathione redox control of asthma: from molecular mechanisms to therapeutic opportunities[J].  Antioxid Redox Signal , 2012 , 17(2):375-408.

[10]Reynaert N L , Glutathione biochemistry in asthma [J]. Biochim Biophys Acta , 2011, 1810(11):1045-1051.

[11] Fitzpatrick A M , Teague WG , Burwell L , et al. Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma [J]. pediatric Research , 2011, 69(2):154-159.

[12] AM Cantin R , Boileau and R Begin. Increased pro colla- gen III aminotermial peptide- related antigens and fibroblast growth signals in the lungs of patients with idiopathic pul - monary fibrosis. Am Rev Respir Dis , 1988, 137(3):572-578.

[13] Chen Xia. Research progress of systemic inflammatory response syndrome[J]. Clinical Medicine Practice, 2010, 19(16):1087-1088.

[14] Wang, Yongmei. Free radicals and glutathione peroxidase[J]. Journal of Pharmacy of the People's Liberation Army, 2005, 21(5):369-371.

[15] Li ZD, Guo T, Wei QP. Healthy "firewall"-glutathione: A guide to drug selection. www.cqvip.com.

[16] Hanana T , Yoshimura A. Regulation of cytokine signaling andinflammation. Cyto GrowFact Rev , 2002, 13 (4 -5): 413 - 421.

[17] Elenkov I J , Iezzoni D G , Daly A , et al. Cytokine dys- regulation , inflammation and well -being. Neuroimmunomodu- lation , 2005, 12(5):255-269.

[18] Schwartsburd P M. Chronic inflammation as inductor of pro-cancermicroenvironment : pathogenesis of dysregulated feed back control.Cancer Metastasis Rev , 2003, 22(1):95-102.

[19] Elenkov I J , Iezzoni D G , Daly A , et al. Cytokine dys- regulation, inflammation and well-being. Neuroimmunomodula- tion , 2005, 12(5):255-269.

[20] Siednienko J , Nowak J , Moynagh P N , et al. Nitric ox- ideaffectsIL -6 expression in human peripheral blood mononuclear cellsinvolving cGMP- dependent modulation of NF-kappa B activity.Cytokine , 2011,54(3):282-288.

[21] Morita R , Uchiyama T , Hori T. Nitric oxide inhibits IFN -alphaproduction of human plasmacytoid dendritic cells partly via aguanosine 3',5'-cyclic monophosphate-dependent pathway. j Immunol, 2005, 175(2):806-812.

[22] Connelly L , Palacios -callender M , Ameixa C , et al. Biphasicregulation of NF-kappa B activity underlies the pro- and anti -inflammatory actions of nitric oxide. j Immunol, 2001, 166(6):3873-3881.

[23] Liu L , Hausladen A , Zeng M , et al. A metabolic en- zyme for S -nitrosothiol conserved from bacteria to humans. Nature , 2001, 410(6827):490-494.

[24] Duan S , Chen C. S-nitrosylation/denitrosylation and apop- tosis ofimmune cells. Cell Mol Immunol , 2007, 4(5):353-358.

[25] Benhar M , Forrester M T , Stamler J S. Protein denitro- sylation: enzymatic mechanisms and cellular functions. Nat Rev Mol Cell Biol , 2009, 10(10): 721-732.

[26] Liu L , Yan Y , Zeng M , et al. Essential roles of S-ni- trosothiols invascular homeostasis and endotoxic shock. Cell, 2004, 116(4):617-628.

[27] Beigi F , GonzalezD R , MinhasK M , et al. Dynamic den- itrosylationvia S -nitrosoglutathione reductase regulates cardio- vascularfunction. proc Natl Acad Sci USA , 2012, 109(11): 4314-4319.

[28] Que L G , Liu L , Yan Y , et al. Protection from experi- mental asthmaby an endogenous bronchodilator. science, 2005, 308(5728):1618-1621.

[29] Tang C H , Wei W , Hanes M A , et al. Increased hepa- tocarcinogenesis from GSNOR deficiency in mice is prevented bypharmacological inhibition of iNOS. Cancer Research, 2013, 73(9):2897-2904.

[30] WU Kai-Yuan, ZHANG Yu-Ying, SU Wen-Ting, et al. Nitrosylated glutathione reductase: a new molecule regulating inflammatory responses[J]. Advances in Biochemistry and Biophysics, 2013, 40(8):731-738.

[31] Zhang YG, Li HM, Zhao B, et al. Efficacy of reduced glutathione in the treatment of mechanically ventilated patients with chronic obstructive pulmonary disease[J]. China Clinical Medicine, 2012, 01: 17-18.

[32] WANG Zhongchen, WANG Guangzheng, LIU Guoqing. Effects of reduced glutathione on liver fibrosis and immune function in patients with hepatitis B[J]. Northwest Journal of Pharmacy, 2019, 34(04): 548-551.

[33] Liu Yajuan, Li Xuesong, Li Qinyuan, et al. Research progress of reduced glutathione in the treatment of immune-related diseases[J]. Journal of Practical Clinical Medicine, 2016, 20(17):205- 208.

[34] Yoshikawa S , King J A , Iausch RN , et al. Acute venti- lator-induced vascular permeability and cytokine responses in isolated and in situ mouse lungs. A ppl Physiol , 2004, 97: 2190-2199.

[35] J Hu, G Hu. Progress in the study of glutathione in Parkinson's disease treatmentProgress in the study of glutathione in Parkinson's disease[J]. Chinese Clinical Pharmacology and Therapeutics, 2008(5):481-484.

[36] He, Quan-Ying. Glutathione and respiratory diseases[J]. Chinese Tuberculosis and Respiratory Journal, 1994(3):138-140.

[37] Lu Huimin, Hu Xiaolei, Jiang Hongmei, et al. Analysis of oxidative stress in patients with systemic lupus erythematosus[J]. Shandong Medicine, 2010, 50(9):60-61.

[38] Wachter A , Wolf S , Steininger H , et al. Differential tar- geting of GSH1 and GSH2 is achieved by multiple transcrip- tion initiation: implications for the compartmentation of glu- tathione biosynthesis in the Brassicaceae [J].  The Plant Jour- nal , 2005, 41(1):15-30.

[39] Newsholme EA , Calder PC. The proposed role of glu- tamine in some cells of the immune system and speculative consequences for the whole animal [J].  Nutrition , 1997, 13(7- 8):728-730.

[40] Jimmy Gutman Md. Glutathione: Your Key to Health. Canada: Kudo, 2004: 201-202.

[41] MAI Meiqi, GUO Chenghong. Role and clinical application of glutathione[J]. Journal of Biochemical Drugs, 1991(2):1-5.

[42] He XW, Zhu LZ. Detoxification effect of glutathione[J]. Foreign medicine: hygiene, 1985(01):7-11.

[43] Iles K , Forman H. Macrophage signaling and respiratory burst. Immune Res , 2002, 26: 95-105.

[44] ZHANG Yuchen, DU Yongli, NIE CuiFang, et al. Clinical application of reduced glutathione Progress[J]. Journal of Community Medicine, 2005(4):26-27.