COVID‐19 예방 및 보조 요법 모두에서 N‐아세틸시스테인(글루타치온)을 사용하는 이유

Rationale for the use of N‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Silvio De Flora  Roumen Balansky

Sebastiano La Maestra

 

First published: 11 August 2020

 

https://doi.org/10.1096/fj.202001807

Abstract 요약

 

COVID‐19는 사이토카인 폭풍, 전신 염증 반응, 면역계 공격으로 인한 폐렴, 급성 호흡곤란 증후군, 심혈관 변화, 다발성 장기부전을 유발할 수 있습니다.

COVID‐19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. 

 

또한 COVID-19 환자에서 산화스트레스 불균형이 발생하는 것으로 입증되었습니다.

Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID‐19 patients. 

 

N-아세틸-L-시스테인 (NAC)은 환원된 글루타티온 (GSH)의 전구체입니다.

N‐ Acetyl‐L‐cysteine (NAC) is a precursor of reduced glutathione (GSH).

 

Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. 

내약성으로 인해, 이 다발성 약물은 점액 용해제는 물론 GSH 고갈 및 산화스트레스와 관련된 다양한 질환의 예방/치료제로 제시되었습니다.

 

NAC는 매우 높은 용량으로 파라세타몰 중독에 대한 해독제로도 사용됩니다.

At very high doses, NAC is also used as an antidote against paracetamol intoxication.

 

Thiols block the angiotensin‐converting enzyme 2 thereby hampering penetration of SARS‐CoV‐2 into cells. 

티올은 안지오텐신-전환 효소 2를 차단하여 SARS‐CoV‐2가 세포로 침투하는 것을 방해합니다.

여기에서 검토한 광범위한 항산화 및 항-염증 메커니즘을 기반으로,

NAC의 경구 투여는 이전에 인플루엔자 및 인플루엔자 유사 질병에 대해 입증된 것처럼 COVID-19 발병 위험을 감소시킬 가능성이 있습니다.

Based on a broad range of antioxidant and anti‐inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID‐19, as it was previously demonstrated for influenza and influenza‐like illnesses. 

 

더욱이 고용량 정맥 주사 NAC는 심각한 COVID-19 사례의 치료와 폐 및 심혈관 부작용 등 치명적 합병증을 제어하는 ​​데 보조 역할을 할 것으로 예상됩니다.

Moreover, high‐dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID‐19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.

Abbreviations

• ACE2 angiotensin‐converting enzyme 2
• ARE antioxidant responsive element
• COPD chronic obstructive pulmonary diseases
• COVID‐19 coronavirus disease‐2019
• COX‐2 cyclooxygenase‐2
• CXCL‐10 chemokine (C‐X‐C motif) ligand 10
• EGFR epidermal growth factor receptor
• GCL glutamate‐cysteine ligase
• GPx glutathione peroxidase
• GR glutathione reductase
• GSH reduced glutathione (γ‐glutamylcysteinylglycine)
• GSH‐C4 N‐butanoyl GSH derivative
• GSSG oxidized glutathione
• HIV human immunodeficiency virus
• HO‐1 heme oxygenase‐1
• hs‐CRP high‐sensitivity C‐reactive protein
• ICAM‐1 intercellular adhesion molecule‐1
• ICU intensive care units
• IL‐ interleukin‐
• L‐Cys L‐cysteine
• LPS lipopolysaccharide
• MAPK p38 p38 mitogen‐activated protein kinase
• MDA malondialdehyde
• MMP‐ matrix metalloproteinase‐
• MPO myeloperoxidase
• NAC N‐acetyl‐L‐cysteine
• NF‐κB nuclear factor kappa‐light‐chain‐enhancer of activated B cells
• NHBECs normal human bronchial epithelial cells
• NKA Na,K‐ATPase
• NO nitric oxide
• NOS nitric oxide synthase
• Nrf2 nuclear factor erythroid 2–related factor 2
• NQO‐1 NAD(P)H dehydrogenase [quinone]‐1
• O2− superoxide radical anion
• OCl hypochlorous acid
• •OH hydroxyl radical
• ONOO− peroxynitrite
• PDI protein disulfide isomerase
• PGE‐2 prostaglandin E‐2
• RO2 peroxyl radical
• ROS
• reactive oxygen species
• RSV respiratory syncytial virus
• SARS‐CoV severe acute respiratory syndrome coronaviruses
• SARS‐CoV‐2 coronavirus responsible for COVID‐19
• Th1 T helper‐1
• TLR3/HA toll‐like receptor 3/hemagglutinin
• T TLR4 toll‐like receptor 4
• TNF tumor necrosis factor
• XNIP inflammasome activator thioredoxin interacting protein

 

1 INTRODUCTION 소개

코로나 바이러스 질병 -2019 (COVID-19) 환자의 약 15%가 가스 교환 및 폐렴 장애를 겪고 있으며, 5%는 중환자실에 입원해야 하는 급성 호흡곤란 증후군 (ARDS), 패 혈성 쇼크 및/또는 다발성 장기 부전을 겪습니다. (ICU) .1

Approximately 15% of coronavirus disease‐2019 (COVID‐19) patients suffer from impairment of gas exchange and pneumonia, and 5% undergo acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure that require hospitalization in intensive care units (ICU).1 

 

ARDS, the leading cause of death in COVID‐19 patients, involves a cytokine storm and a systemic inflammatory response resulting from the release of large amounts of pro‐inflammatory cytokines and chemokines that trigger an attack by the immune system.2 

코로나 19 환자의 주요 사망 원인인 ARDS는 사이토카인 폭풍과 면역계의 공격을 유발하는 다량의 친-염증성 사이토카인과 케모카인의 방출로 인한 전신 염증 반응을 수반합니다. 2 

 

COVID‐19는 호흡기 계통에 영향을 미치는 것 외에도, 심혈관 계통 등 다른 계통에도 영향을 미치며, 확산성 혈전증은 COVID‐19 환자의 부작용에 대한 중요한 기여자로 부상하고 있습니다. 

Besides affecting the respiratory system, COVID‐19 affects other systems, also including the cardiovascular system, and diffuse thrombosis is emerging as an important contributor to adverse outcomes in patients with COVID‐19.

 

Different pathogenic disturbances are involved, such as acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction;

다양한 병원성 장애는, 빈맥, 저혈압, 저산소 혈증으로 인한 심근 수요 및 공급의 급격한 변화 등과 관련되어, 제2형 심근 경색을 유발합니다;

 

acute coronary syndrome due to acute atherothrombosis in a virally induced thrombotic and inflammatory milieu;

바이러스로 유도된 혈전 및 염증성 환경에서 급성 죽상혈전증으로 인한 급성 관상동맥 증후군; 

 

microvascular dysfunction due to diffuse microthrombi or vascular injury;

미만성 미세혈전 또는 혈관 손상으로 인한 미세혈관 기능 장애; 

 

stress‐related cardiomyopathy (Takotsubo syndrome); direct viral cardiomyocyte toxicity and myocarditis.3 

스트레스-관련 심근병증 (타코츠보 증후군); 직접적 바이러스성 심근세포 독성 및 심근염.3 

 

이러한 모든 합병증은 바이러스 감염에 의해 자극된 염증 반응을 반영합니다.
All of these complications reflect inflammatory reactions stimulated by the viral infection.

 

COVID‐19 is particularly severe in individuals who are at risk either because of old age or of pre‐existing pathological conditions.

COVID‐19는 노령이나 기존 병리적 상태로 인해 위험에 처한 개인에게 특히 심각합니다. 

 

For instance, in Italy the mean age of patients dying of COVID‐19 as of May 28 was 80 years, and 95.9% of deceased persons had important pre‐existing conditions, such as cardiovascular diseases, cerebrovascular diseases, diabetes, dementia, chronic obstructive pulmonary diseases (COPD), cancer, chronic liver disease, chronic renal failure, respiratory failure, human immunodeficiency virus (HIV) infection, autoimmune diseases, and obesity.

예를 들어 이탈리아에서는 5월 28일 현재 COVID-19로 사망한 환자의 평균 연령이 80세였으며 사망자의 95.9%는 심혈관 질환, 뇌 혈관 질환, 당뇨병, 치매, 만성 폐쇄성 질환(COPD), 암, 만성 간 질환, 만성 신부전, 호흡 부전, 인체 면역 결핍 바이러스 (HIV) 감염, 자가면역 질환 및 비만과 같은 중요한 기저 질환을 갖고 있었습니다. 

 

Specifically, 14.9% had a single comorbidity, 21.5% had 2 comorbidities, and 59.5% had 3 or more comorbidities, with a mean number of 3.3 comorbidities.4 

구체적으로 14.9%는 단일 합병증, 21.5%는 2개의 합병증, 59.5%는 3개 이상의 합병증으로 평균 3.3개의 합병증을 가졌습니다.

 

특히 80세 미만 환자의 경우, 남성이 치명적 사례가 훨씬 더 많았는데, 이들은 혈중 감소된 글루타티온 (GSH) 수치가 낮았습니다.

Especially in patients below the age of 80, the fatal cases were much more frequent in men,4 who have lower levels of blood reduced glutathione (GSH).5 

 

노인들은 산화스트레스 및 염증성 사이토카인 생성과 관련된 만성 낮은 수준의 염증을 유지하며, 이 상태는이 집단에서 바이러스 감염의 심각성을 증가시키며 항산화제를 투여하면 약화될 수 있습니다.

Elderly individuals maintain a chronic low level of inflammation that is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population and that could be attenuated by administration of antioxidants.6

Rationale for the use of N‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

A significant elevation in blood serum glutathione reductase (GR), resulting from oxidative stress imbalance, was detected in COVID‐19 patients, especially when admitted to ICU.7 

특히 ICU에 입원했을 때, COVID-19 환자에서 산화스트레스 불균형으로 인한 혈청 글루타티온 환원효소 (GR)의 현저한 증가가 발견되었습니다.7 

 

문헌 데이터의 축적에서, GSH의 체내 결핍이 심각한 증상과 COVID-19로 인한 사망의 기초가 될 수 있습니다. 

From an accumulation of literature data, an endogenous deficiency in GSH may underlie the serious manifestations and death from COVID‐19.8 

 

As we will discuss below, N‐acetyl‐L‐cysteine (NAC) is used in a broad range of conditions to restore or protect against GSH depletion and has a wide safety margin. 

아래에서 논의할 바와 같이 N-아세틸-L-시스테인 (NAC)은 GSH 고갈을 복원하거나 보호하기 위해 광범위한 조건에서 사용되며 넓은 안전 여유가 있습니다. 

 

다른 원인으로 인한 ARDS 치료에 도움이 되었으며 COVID-19 환자의 폐 손상을 제한하거나 예방할 수 있습니다.

이 제안에 대한 증거는 여기에서 검토됩니다.

It has been of benefit in treating ARDS from other causes and might limit or prevent lung damage in patients with COVID‐19. The evidence for this proposal is reviewed here.

 

글루타티온 전문

www.cantox.kr  

Heath Mall

 

 

 

2 INHIBITION BY THIOLS OF SARS‐COV‐2 BINDING TO CELLS

세포에 결합하는 SARS‐COV‐2의 THIOLS에 의한 억제

안지오텐신-전환 효소 2 (ACE2)는 중증 급성 호흡기 증후군 (SARS) 코로나 바이러스의 기능 수용체로, COVID-19의 원인 인 SARS‐CoV 및 SARS‐CoV‐2의 세포로의 유입을 담당합니다. 

The angiotensin‐converting enzyme 2 (ACE2) is the functional receptor for severe acute respiratory syndrome (SARS) coronaviruses, responsible for entrance into cells of both SARS‐CoV and SARS‐CoV‐2, the etiological agent of COVID‐19.9 

 

Therefore, the interaction of viral spike proteins with ACE2 is a critical step in the viral replication cycle. 

따라서 바이러스 스파이크 단백질과 ACE2의 상호작용은 바이러스 복제주기에서 중요한 단계입니다. 

 

바이러스 스파이크 단백질과 ACE2의 수용체 결합 도메인에는 몇 가지 시스테인 잔기(residues)가 있습니다. 

The receptor binding domain of the viral spike proteins and ACE2 has several cysteine residues. 

 

분자 동적 시뮬레이션은 ACE2 및 SARS-CoV/CoV-2 스파이크 단백질의 모든 이황화 결합이 티올 그룹으로 감소되었을 때 결합 친화성이 현저하게 손상되었음을 보여주었습니다. 

Molecular dynamic simulations showed that the binding affinity was significantly impaired when all the disulfide bonds of both ACE2 and SARS‐CoV/CoV‐2 spike proteins were reduced to thiol groups.

 

These findings are consistent with the view that the reduction of disulfides into sulfhydryl groups completely impairs the binding of SARS‐CoV/CoV‐2 spike protein to ACE2 (see Figure 1) and provide a molecular basis for the severity of COVID‐19 infection due to oxidative stress.10 

이러한 발견은 이황화물을 sulfhydryl 그룹으로 환원하면 SARS-CoV/CoV-2 스파이크 단백질이 ACE2에 결합하는 것을 완전히 손상시키고, COVID-19 감염의 중증도에 대한 분자적 근거를 제공한다는 견해와 일치합니다. 

 

또한, 동물연구와 임상연구 모두에서 질산염에 대한 내성을 약화시키는 것으로 알려진 NAC의 보충이 생체내에서 레닌/안지오텐신 시스템의 기능을 수정한다고 제안했습니다. 

Furthermore, both animal studies and clinical studies suggested that supplementation of NAC, which is known to attenuate the tolerance to nitrates, modifies the function of the renin/angiotensin system in vivo.

 

Such an effect is probably mediated by inhibition of ACE activity.11 

이러한 효과는 아마도 ACE 활동의 억제에 의해 매개 될 것입니다 .11 

 

ACE를 차단함으로써 NAC는 SARS-CoV-2 감염에서 잠재적으로 유용한 활동인 안지오텐신 II의 유해한 영향으로부터 보호할 수 있습니다.12

By blocking ACE, NAC may provide protection from the deleterious effects of angiotensin II, a potentially useful activity in SARS‐CoV‐2 infection.12

FIGURE 1 Open in figure viewer

Major mechanisms involved in the antioxidant and anti‐inflammatory action of NAC via GSH (modified and updated from Sadowska, 201214). The blue arrows indicate stimulation of downstream activities or pathways, whereas the T‐shaped symbols indicate inhibition of downstream activities or pathways. See Text for details, references, and meaning of acronyms

3 GLUTATHIONE (글루타티온) AND N‐ACETYL‐L‐CYSTEINE

감소된 글루타티온 (GSH)은 인체와 모든 생명체의 주요 방어 메커니즘입니다.

Reduced glutathione (GSH) is a major defense mechanism of the human body and all living beings. 

 

그러나 트리펩타이드 (γ-glutamylcysteinylglycine)이기 때문에 세포에 잘 침투하지 못합니다.

However, being a tripeptide (γ‐glutamylcysteinylglycine), it poorly penetrates cells.

 

L‐cysteine (L‐cys) is the rate‐limiting amino acid in GSH synthesis. 

L-시스테인 (L-cys)은 GSH 합성에서 속도-제한 아미노산입니다.

 

NAC는 탈아세틸화된 세포에 쉽게 침투하여 L-cys를 생성하여 GSH 합성을 촉진합니다.

NAC easily penetrates cells where it is deacetylated to yield L‐cys thereby promoting GSH synthesis.

 

Therefore, NAC works per se in the extracellular environment and as a precursor of GSH inside cells. 

따라서 NAC는 세포 외 환경에서 그 자체로 작동하며 세포 내부의 GSH의 전구체로 작용합니다.

 

Accordingly, all its intracellular effects are mediated by GSH replenishment.

따라서 모든 세포 내 효과는 GSH 보충에 의해 매개됩니다.

 

GSH의 재활용은 증가하지만 COVID-19 폐 질환의 높은 소비량을 따라갈 수 없습니다.

Recycling of GSH increases but cannot match the high consumption in COVID‐19 lung disease.

 

This requires new GSH synthesis, which increases enormously, largely through activation and up‐regulated production of glutamate‐cysteine ligase (GCL), the rate‐limiting enzyme for GSH biosynthesis that in turn depends on the availability of intracellular L‐cys, the rate‐limiting substrate for the enzyme.13 

이를 위해서는 GSH 생합성을 위한 속도제한 효소인 글루타메이트-시스테인 리가제 (GCL)의 활성화 및 상향조절된 생산을 통해 엄청나게 증가하는 새로운 GSH 합성이 필요합니다.

 

NAC는 GSH보다 경구 및 국소 생체 이용률이 더 우수하고 안전성이 뛰어납니다.

NAC has better oral and topical bioavailability than GSH, and has an excellent safety profile.

 

그러나 경구 투여 후 NAC의 전신 생체 이용률은 상대적으로 낮습니다.

 However, the systemic bioavailability of NAC after oral administration is relatively poor.14 

 

This thiol has been in clinical use since the 1960s as a mucolytic agent, usually at the oral dose of 600 mg, due to its ability to break the disulfide bonds of mucus and depolymerize mucin.

이 티올은 점액의 이황화 결합을 파괴하고 뮤신을 분해하는 능력으로 인해, 일반적으로 600mg의 경구 투여량으로 점액 용해제로 1960 년대부터 임상적으로 사용되었습니다. 

 

 

As previously mentioned, breaking disulfide bonds into thiol groups may also reduce the affinity for the virus to attach to ACE2 sites.9 

앞서 언급했듯이 이황화 결합을 티올 그룹으로 분리하면 바이러스가 ACE2 부위에 부착하는 친화성을 감소시킬 수 있습니다.

 

NAC is also used in nebulized format in patients with acute bronchopulmonary disease, such as pneumonia, bronchitis, and tracheobronchitis. 

NAC는 폐렴, 기관지염 및 기관지염과 같은 급성 기관 지폐 질환 환자에서 분무 형식으로도 사용됩니다.

 

또한 NAC는 WHO 필수 의약품 모델 목록에 중독 해독제로 인용되었습니다.

Moreover, NAC is quoted in the WHO Model List of Essential Medicines as an antidote in poisonings.

 

At doses as high as 150 mg/kg intravenously, NAC is extensively used and is in standard practice as a clinically approved antidote against paracetamol (acetaminophen) intoxication, and it is almost 100% effective if given within 8 hours postingestion.15 

150m/kg의 높은 용량을 정맥 내로 투여하면 NAC가 광범위하게 사용되고 파라세타몰 (아세트아미노펜) 중독에 대한 임상 적으로 승인된 해독제로 표준 실무에 있으며 게시 후 8시간 이내에 투여하면 거의 100% 효과적입니다.

 

파라세타몰 과다 복용이 있을 수 있으며, 미토콘드리아 산화 불균형과 질화 스트레스를 유발하여 많은 국가에서 급성 간 기능 부전의 가장 흔한 원인인 간 손상을 유발합니다.

Paracetamol overdosage may cause mitochondrial oxidative imbalance and nitrosative stress leading to liver injury, which is the most common cause of acute liver failure in many countries.16 

 

NAC의 정맥 투여는 또한 염증성 질환 인 조영제 유발 신 병증을 예방하는 데 사용됩니다.

The intravenous administration of NAC is also used to prevent contrast‐induced nephropathy that, again, is an inflammatory condition.15

또한, 이 다발성 약물은 자유라디칼 생성을 유발하는 다양한 물질의 독성을 약화시키고, GSH 고갈 및 심장질환, 당뇨병, AIDS, 신경퇴행성 질환, 신경정신병 및 기타 여러 질환과 같은 산화 환원 상태 변화와 관련된 다양한 질병의 치료 및/또는 예방을 위해 제안되었습니다. , 

In addition, this pleiotropic drug has been proposed to attenuate the toxicity of various agents that cause the generation of free radicals as well as for the therapy and/or prevention of a variety of diseases involving GSH depletion and redox status alterations, such as heart diseases, diabetes, AIDS, neurodegenerative diseases, neuropsychiatric disorders, and several other conditions.14, 17

4 OXIDATIVE STRESS, INFLAMMATION, AND IMMUNE RESPONSE

산화 스트레스, 염증 및 면역 반응

 

 

산화스트레스와 염증은 엄격하게 상호연관되어 있습니다. 

Oxidative stress and inflammation are strictly inter‐related.

 

Exposure of cells either to the hydroxyl radical (•OH) or the superoxide radical anion (O2•−) induces a dose‐dependent release of pro‐inflammatory cytokines.

세포가 하이드록실 라디칼 (• OH) 또는 수퍼 옥사이드 라디칼 음이온 (O2 •-)에 노출되면, 친-염증성 사이토카인의 용량 의존적 방출이 유도됩니다.

 

Lipopolysaccharide (LPS)는 활성산소종 (ROS)의 세포내 축적을 유도하고, 인터루킨 (IL) -1 베타, IL-6 및 종양 괴사 인자-알파 (TNF-α)의 방출을 증가시킵니다. 

Lipopolysaccharide (LPS) induces intracellular accumulation of reactive oxygen species (ROS) and augments the release of interleukin (IL)‐1beta, IL‐6, and tumor necrosis factor‐alpha (TNF‐α).

 

A kappa B (κB‐α)/nuclear factor kappa B (NF‐κB)‐independent pathway mediates the redox‐dependent regulation of inflammatory cytokines, and this process is enhanced by GSH depletion.18

카파 B (κB-α)/핵 인자 카파 B (NF-κB) 독립 경로는 염증성 사이토카인의 산화환원 의존적 조절을 매개하며, 이 과정은 GSH 고갈에 의해 강화됩니다.

GSH를 포함한 ROS 및 티올 항산화제는 광범위한 문헌에 기록된 바와 같이 다양한 수준에서 타고난 면역을 조절합니다. 

ROS and thiol antioxidants, including GSH, regulate innate immunity at various levels, as documented by a broad literature.

 

GSH is not only important as an antioxidant, but also as a signaling molecule in the redox‐sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection.19 

GSH는 항산화제로서 중요 할뿐만 아니라 염증 및 감염에 대한 숙주 방어와 관련된 세포 기전의 산화환원에 민감한 단계에서 신호 분자로도 중요합니다.

 

GSH는 면역 과정에 관련된 특정 요인에 영향을 미칠뿐만 아니라, 그러나 그것은 또한 열과 같은 복잡한 면역반응을 수정하고 열 유도가 산화스트레스와 관련이 있음을 시사하는 데이터가 있습니다. 

It is noteworthy that GSH not only affects certain factors involved in immunological processes, but it also modifies complex immune reactions such as fever, and there are data suggesting that fever induction is associated with oxidative stress.20 

 

보체 시스템은 감염원으로부터 보호하는 타고난 면역반응의 핵심 매개체이지만, 또한 중요한 역할을 합니다. 

Although the complement system is a key mediator of the innate immune response that protects against infectious agents, it also plays a critical role in promoting the inflammatory process that leads to tissue injury.21 

 

In particular, complement may be involved in coronavirus pathogenesis, as inferred from the finding that C3 knockout mice infected with SARS‐CoV have less lung disease than wild‐type mice.22 

특히, SARS-CoV에 감염된 C3 녹아웃 쥐가 야생형 쥐보다 폐 질환이 적다는 사실에서 추론된 것처럼 보체는 코로나 바이러스 발병에 관여할 수 있습니다.

 

예비 데이터는, 중간정도 질환 환자보다 중증 질환 환자에서, COVID‐19 환자에서 혈장 수치가 상당히 높은 보체 (sC5b‐9 및 C5a) 활성화에 대한 증거를 제공합니다. 

Preliminary data provide evidence for activation of complement (sC5b‐9 and C5a) in patients with COVID‐19, with significantly higher plasma levels in the patients with severe disease than in those with moderate disease.

 

따라서 보체 활성화는 COVID-19.21에서 새로운 치료 목표로 제안되었습니다. 

Hence, complement activation has been suggested as a novel therapeutic target in COVID‐19.21 

 

In this context, it is noteworthy that administration of NAC (2 × 600 mg/day for 8 weeks) in a placebo‐controlled study has been shown to reduce the plasma levels of inflammatory markers, including complement (C3), in peritoneal dialysis patients.23

이러한 맥락에서 위약 대조 연구에서,  복막 투석 환자에서 보체 (C3) 등 염증 표지자의 혈장 수준 NAC (8 주 동안 2 x 600mg/일) 투여가 감소하는 것으로 나타났습니다. 

생체 분자 손상을 일으키는 만성 산화스트레스는 면역 기능을 포함한 생리 기능의 노화 관련 감소에 기여합니다. 

Chronic oxidative stress, causing biomolecular damage, contributes to the age‐related decline in physiological functions, including the immune function.

 

폐경 후 여성에게 NAC (600mg)를 매일 투여하면 면역 방어력이 강화되어 여러 림프구 기능 (유착, 화학 주성, 증식 및 자연 살해), 활성 및 호중구 기능 (유착, 화학 주성, 식균 작용, 과산화물) 및 사이토카인 수준 (IL-2, IL-8 및 TNF-α)을 모니터링하여 알 수 있듯이, 감염과 같은 노화시 면역계 관련 질병의 확률이 감소했습니다. 

The daily administration of NAC (600 mg) to postmenopausal women strengthened the immune defenses thereby decreasing the probability of immune system‐related diseases in aging, such as infections, as shown by monitoring several lymphocyte functions (adherence, chemotaxis, proliferation, and natural killer activity) and neutrophil functions (adherence, chemotaxis, phagocytosis, and superoxide) as well as cytokine levels (IL‐2, IL‐8, and TNF‐α).24

 

5 ANTIOXIDANT AND ANTI‐INFLAMMATORY MECHANISMS OF NAC

NAC는 세포 내부에서 GSH 보충에 의해 매개되는 다양한 메커니즘을 통해 작동합니다. 주요한 것은 친 핵성인데, 이는 직접적으로 또는 GSH S- 전이 효소를 통해 친 전자 성 대사 산물과 반응하는 설 프히 드릴 기 (-SH)의 능력으로 구성됩니다 .17이 특성은 DNA 반응성 대사 산물이 결합하고 반응성 중간체를 차단합니다. 반응성 중간체의 예는 사이토 크롬 P450 효소를 통해 형성된 파라세타몰 대사 산물 N- 아세틸 -p- 벤조 퀴논 이민 (NAPQI)입니다. 또한 NAC는 p53 매개 세포 자멸사를 통해 항산화 활성을 발휘할 수 있습니다 .NAC 이화 작용에 의해 파생 된 L-Cys는 혈관 확장제, 항염증제 및 쉽게 확산 가능한 황화수소로 쉽게 생체 전환됩니다. 따라서 NAC는 황화수소 공여자로 간주되어야합니다 .26 

 

NAC works via a broad variety of mechanisms, which inside cells are mediated by GSH replenishment. A major one is its nucleophilicity, which consists of the ability of sulfhydryl groups (–SH) to react with electrophilic metabolites, either directly or via GSH S‐transferases.17 This property results in binding of DNA reactive metabolites and in blocking reactive intermediates. An example of reactive intermediate is the paracetamol metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI) formed via cytochrome P450 enzymes. In addition, NAC can exert antioxidant activity via p53‐mediated apoptosis.25 L‐Cys, derived by NAC catabolism, is readily bioconverted to the vasodilator, anti‐inflammatory and readily diffusible hydrogen sulfide. Therefore, NAC should be regarded as a hydrogen sulfide donor.26

Rationale for the use of N‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

 

NAC의 항산화 / 항 염증 특성을 담당하는 몇 가지 주요 메커니즘이 그림 1에 요약되어 있습니다. 우선, NAC가 ROS, 특히 차아 염소산 (HOCl) 및 • OH.27 NAC에 의한 ROS 생성 혈관 NAD (P) H 산화 효소의 억제는 고혈압 예방 및 죽상 경화증과 같은 통제되지 않은 성장 및 염증과 관련된 병리학 적 상태와 관련이 있습니다 .28 NAC 분자 내의 SH- 그룹은 또한 지질, 단백질 및 DNA의 산화에 중요한 역할을하는 몇 가지 반응성 질소 종 (RNS)을 제거합니다 .29 NAC는 혈관 확장제와 산화 질소의 응집 방지 효과를 강화합니다. 이는 임상 적으로 매우 중요한 상호 작용이며 다음과 같은 것으로 나타났습니다. 급성 심부전 및 급성 심근 허혈 및 경색의 맥락에서 가치가 있습니다 .30
Some major mechanisms responsible for the antioxidant/anti‐inflammatory properties of NAC are summarized in Figure 1. First of all, it has been established for a long time that NAC is a potent scavenger of ROS and especially of hypochlorous acid (HOCl) and •OH.27 Inhibition by NAC of the ROS‐producing vascular NAD(P)H oxidases is relevant to prevention of hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.28 The SH‐groups within the NAC molecule can also scavenge several reactive nitrogen species (RNS) that play a role in the oxidation of lipids, proteins, and DNA.29 NAC potentiates the vasodilator and antiaggregatory effects of nitric oxide, which is a very important interaction clinically, and which has been shown to be valuable in the context of acute heart failure and acute myocardial ischemia and infarction.30

 

 

Inhibition by NAC of epidermal growth factor receptor (EGFR), a tyrosine kinase involved in inflammation,14, 31 also results in a decreased inactivation of α1‐antitrypsin. In particular, NAC has the ability to improve the efficacy and structural conformational integrity of α1‐antitrypsin via a GSH‐mediated mechanism, and it enhances α1‐antitrypsin transcytosis thus improving its cellular uptake and functions.32 In experimental studies, the oral administration of NAC to pregnant mice enhanced the expression of the gene encoding for an α1‐antitrypsin precursor in the fetal liver.33 Together with redox imbalance, α1‐antitrypsin deficiency is involved in the pathogenesis of COPD. NAC was found to reduce IL‐8 levels, normalized C‐reactive protein (CRP) levels, and improved clinical outcomes in patients with COPD exacerbations.34 A prospective, randomized, controlled trial in the Shandong Province, China enrolling adult bronchiectasis patients with at least two exacerbations in the previous year showed that oral NAC (600 mg twice daily for 12 months) was able to reduce the risk of exacerbations.35

염증과 관련된 티로신 키나아제 인 표피 성장 인자 수용체 (EGFR)의 NAC에 의한 억제는 또한 α1- 항 트립신의 불 활성화를 감소시킵니다. 

특히 NAC는 GSH 매개 메커니즘을 통해 α1- 항 트립신의 효능 및 구조적 형태 무결성을 개선 할 수 있으며 α1- 항 트립신 트랜스 사이토 시스를 강화하여 세포 흡수 및 기능을 향상시킵니다 .32 실험 연구에서 경구 투여는 임신 한 생쥐에 대한 NAC는 태아 간에서 α1- 항 트립신 전구체를 암호화하는 유전자의 발현을 향상 시켰습니다 .33 산화 환원 불균형과 함께 α1- 항 트립신 결핍은 COPD의 병인에 관여합니다. NAC는 IL-8 수준을 낮추고, CRP (C 반응성 단백질) 수준을 정상화하고, COPD 악화 환자의 임상 결과를 개선하는 것으로 밝혀졌습니다 .34 중국 산둥성에서 진행된 전향 적 무작위 대조 시험에서 성인 기관지 확장증 환자를 전년도에 최소 2 건의 악화로 인해 경구 NAC (12 개월 동안 매일 두 번 600mg)가 악화 위험을 줄일 수있었습니다 .35

또한 NAC는 ARDS에 보호 효과가있는 것으로 나타났습니다. ROS가 급성 폐 손상의 발병 기전에 핵심적인 역할을하고 ARDS 환자의 폐포 상피 내막 액이 GSH가 부족하여 이러한 환자가 해당 질병에 걸리기 쉬운 것으로 잘 알려져 있습니다 .36 무작위, 이중 맹검 , 미국과 캐나다의 5 개 ICU에서 위약 대조, 전향 적 임상 시험에서 NAC (70mg / kg 체중)를 10 일 동안 8 시간마다 정맥 투여하면 적혈구에서 GSH를 효과적으로 보충하여 그 수가 감소한 것으로 나타났습니다. 급성 폐 손상 일수의 일수, 심장 지수를 크게 증가 시켰습니다 .37 NAC (6 일 동안 5 % 덱 스트로스 250mL에서 체중 50mg / kg)가 만료 된 에탄과 말론 디 알데히드를 측정하여 평가 한 바와 같이 ARDS 환자의 폐를 보호했습니다. (MDA), GSSG 및 GSH in the epithelial lining fluid.38 또 다른 연구에서, NAC (첫날 150mg / kg 체중, 3 일 동안 50mg / kg)를 투여받은 ICU에 입원 한 환자는 비교했을 때 더 나은 임상 결과 위약 그룹의 환자와 함께. 또한 NAC는 세포 외 총 항산화 력과 총 티올 분자를 증가 시켰습니다 .39

In addition, NAC has been shown to have protective effects in ARDS. It is well established that ROS play a key role in the pathogenesis of the acute lung injury and that the alveolar epithelial lining fluid of patients with ARDS is deficient in GSH, which may predispose these patients to that disease.36 A randomized, double‐blind, placebo‐controlled, prospective clinical trial in 5 ICUs in the USA and Canada showed that the intravenous administration of NAC (70 mg/kg body weight), every 8 hours for 10 days, effectively repleted GSH in red blood cells, decreased the number of days of acute lung injury, and significantly increased the cardiac index.37 NAC (50 mg/kg body weight in 250 mL of 5% dextrose for 6 days) protected the lungs of ARDS patients, as evaluated by measuring the expired ethane and malondialdehyde (MDA) as well as GSSG and GSH in the epithelial lining fluid.38 In another study, patients hospitalized in ICU who received NAC (150 mg/kg body weight on the first day, followed by 50 mg/kg for 3 days) had a better clinical outcome as compared with patients in the placebo group. Moreover, NAC increased extracellular total antioxidant power and total thiol molecules.39

추가 메커니즘은 NAC가 산화 스트레스에 의해 핵 인자 적혈구 계 2 관련 인자 2 (Nrf2)의 자극을 더욱 강화한다는 것입니다 .40 이는 2 상 효소 유전자의 전사를 촉진하고 염증을 하향 조절합니다. 실제로 Nrf-2는 헴 옥 시게나 제 1 (HO-1), NAD (P) H 탈수소 효소 [퀴논] 1 (NQO-1)과 같은 내인성 항산화 효소의 항산화 반응 요소 (ARE) 매개 유도에 필수적입니다. 그리고 GCL.41 흥미롭게도 헴-헴 옥 시게나 제 시스템을 표적으로 삼아 COVID-19 감염 후 심각한 합병증을 예방할 수 있다고 제안되었습니다 .42 동시에 NAC는 산화 스트레스 매개 핵 인자 카파-경쇄-인핸서 활성화를 억제합니다. 활성화 된 B 세포 (NFκB) 및 전 염증성 유전자를 상향 조절하는 생화학 적 경로 .14 NAC는 또한 세포 내 과산화수소 농도를 감소시키고 NFκB가 세포핵으로의 전좌와 p38 미토 게의 인산화를 억제함으로써 세포 내 총 티올 함량을 복원했습니다.

 

 

A further mechanism is that NAC further enhances the stimulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) by oxidative stress,40 which favors transcription of phase II enzyme genes and downregulates inflammation. In fact, Nrf‐2 is essential for the antioxidant responsive element (ARE)‐mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO‐1), NAD(P)H dehydrogenase [quinone] 1 (NQO‐1), and GCL.41 Interestingly, it has been proposed that targeting the heme‐heme oxygenase system may prevent severe complications following COVID‐19 infection.42 In parallel, NAC inhibits the oxidative stress‐mediated activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) and biochemical pathways upregulating pro‐inflammatory genes.14 NAC also reduced the intracellular hydrogen peroxide concentration and restored the intracellular total thiol contents by inhibiting NFκB translocation to the cellular nucleus and phosphorylation of p38 mitogen‐activated protein kinase (MAPK p38).43 In influenza infection, NAC inhibits the induction of pro‐inflammatory cytokine response through endosomal toll‐like receptor 3/hemagglutinin (TLR3/HA)‐induced, ROS‐dependent NFκB activation.44

Furthermore, NAC has anti‐inflammatory activity independently of its antioxidant activity, as shown by the finding that it inhibited the LPS‐mediated neurogenic inflammation by counteracting the release of Na,K‐ATPase (NKA), a marker for cell necrosis, which could explain the fall in IL‐6 with NAC.45 A multicenter, randomized, placebo‐controlled trial, sequentially testing early use of intravenous NAC, followed by oral ramipril for 12 weeks, is based on the rationale that these agents have the ability to limit nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein (TXNIP).46

6 ROLE OF GSH AND PROTECTIVE EFFECTS OF NAC IN INFLUENZA AND OTHER VIRAL DISEASES. EXPERIMENTAL FINDINGS AND CLINICAL TRIALS

NAC has been demonstrated to attenuate the incidence and severity of influenza and influenza‐like illnesses. It was tested in a double‐blind trial, involving 20 Italian Centers, which enrolled 262 subjects of both sexes randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Moreover, only 25% of A/H1N1 influenza virus‐infected subjects under NAC treatment developed a symptomatic form vs 79% in the placebo group.47

Infection by RNA viruses induces oxidative stress in host cells, and growing evidence indicates that viral replication is regulated by the redox state of the host cell and that the GSH content contributes to downregulate influenza virus replication.48 An experimental study showed that GSH decreased the production of influenza virus particles in canine kidney cells or human small airway epithelial cells, where it inhibited the expression of viral matrix protein, caspase activation, and Fas upregulation. Moreover, administration of GSH with the drinking water to BALB/c mice decreased the viral titer in both lung and trachea 4 days after intranasal inoculation of the mouse‐adapted influenza strain A/X‐31.49

It has also been demonstrated that NAC inhibits virus replication and expression of pro‐inflammatory molecules in adenocarcinoma human alveolar basal epithelial (A549) cells infected by the highly pathogenic H5N1 influenza virus.50 NAC inhibited the pulmonary inflammation and edema as well as myeloperoxidase (MPO) activity, total cells, neutrophils, macrophages, TNF‐α, IL‐6, IL‐1β, and chemokine (C‐X‐C motif) ligand‐10 (CXCL‐10) in the bronchoalveolar lavage fluid and reduced the levels of toll‐like receptor 4 (TLR4) protein and mRNA in the lungs of BALB/c mice inoculated intranasally with A/swine/HeBei/012/2008/ H9N2 influenza virus.51 A study in the same strain of mice showed that old animals had lower GSH concentrations than young animals in spleen, lymph nodes, lungs, and pancreas. The gene expression of endoplasmic reticulum stress markers involved in GSH metabolism and folding of proteins, such as Nrf2 and protein disulfide isomerase (PDI), was reduced in the lung of old mice. Treatment with the N‐butanoyl GSH derivative (GSH‐C4) of old mice infected with influenza A PR8/H1N1 virus increased GSH content in organs, reduced viral replication, and induced an immune response, in particular the Th1 (T helper‐1) cytokine profile.52

Influenza A and B viruses and respiratory syncytial virus (RSV) are responsible for COPD by increasing inflammatory and apoptosis events through mechanisms involving ROS generation and release of mucins from epithelial cells. NAC inhibited the replication of these viruses and restored the normal functions of alveolar type II A549 cells by modulating MUC5AC overexpression and release and by inhibiting IL‐8, IL‐6, and TNF‐ α as well as NF‐κB translocation to the nucleus and phosphorylation of MAPK p38.53

Furthermore, it has been known for almost 30 years that GSH plays an important defense role against HIV and that NAC may exert protective effects toward this viral infection. For instance, in agreement with data obtained in cells exposed to herpesvirus type 1 (DNA virus) or to Sendai (an RNA virus belonging to the family of Paramyxoviridae), it was shown that GSH inhibits HIV envelope glycoproteins (gp120) and interferes with late stages of virus replication in chronically infected macrophages, a known reservoir of the virus in the body.54 Both GSH and NAC inhibited the induction of HIV‐1 expression in a chronically HIV‐1‐infected promonocytic cell line (U1/HIV) and in human primary monocyte/macrophages cultured in vitro, where both thiols decreased HIV‐1 p24 antigen levels as well as reverse transcriptase activity.55

Interestingly, NAC appears to synergize with antivirals in the protection toward influenza in mouse models, as shown with ribavirin56 and oseltamivir.57

7 NAC IN SMOKERS

Smokers are more vulnerable to infectious diseases, as shown in the case of influenza and of the MERS‐CoV outbreak. An analysis of the literature suggests that smoking is most likely associated with the negative progression and adverse outcomes of COVID‐19.58 Exposure to cigarette smoke increases ROS levels and causes a drop in GSH intracellular concentrations.59 Aldehydes in cigarette smoke deplete the total available GSH pool by reacting to form nonreducible GSH‐aldehydes derivatives.60 GSH depletion accelerates cigarette smoke‐induced inflammation and airspace enlargement, and the GSH adaptive response declines with age.61

By increasing GSH production, NAC has the ability to modulate a large variety of smoking‐related end‐points and cancer in experimental test systems, due to many interconnected mechanisms and properties.17, 62 In addition, NAC was shown to attenuate several biomarker alterations in a randomized, double‐blind, placebo‐controlled, Phase II chemoprevention trial in heavy smokers who received NAC tablets (600 mg) twice daily for 6 months.63

8 CONCLUSIONS

NAC is approved by FDA under various formulations and is popular as a health supplement, this molecule having been proposed as a nutraceutical that might aid the control of RNA viruses including influenza and coronavirus.64-66 

NAC는 다양한 제형으로 FDA의 승인을 받았으며 건강보조식품으로 인기가 있으며, 이 분자는 인플루엔자 및 코로나 바이러스 등 RNA 바이러스의 제어에 도움이 될 수 있는 기능 식품으로 제안되었습니다.

 

Almost 60 years of experience in the prophylaxis and therapy of a variety of clinical conditions have established the safety of this drug, even at very high doses and for long‐term treatments.

예방 및 치료 분야에서 거의 60년의 경험 다양한 임상조건이 매우 고용량 및 장기 치료에서도 이 약물의 안전성을 확립했습니다.

 

Drug repurposing is the fastest strategy toward an effective and accessible treatment against COVID‐19 before a vaccine is available,67 and molecules working via multiple mechanisms of action, such as NAC, are more likely to be effective as compared with drugs having a single target.

약물용도변경은 백신을 사용할 수 있기 전에 COVID-19에 대한 효과적이고 접근가능한 치료를 위한 가장 빠른 전략이며, NAC 같은 여러 작용 메커니즘을 통해 작동하는 분자는 단일 표적을 가진 약물에 비해 더 효과적일 가능성이 높습니다.

여기에서 논의된 기계론적 전제를 기반으로 NAC는 COVID-19의 예방과 치료 모두에서 제안될 수 있습니다. 

Based on the herein discussed mechanistic premises, NAC may be proposed both in the prevention and in the therapy of COVID‐19. 

 

특히, NAC의 경구 투여는, 1일 2회 600mg의 용량으로, 이전에 인플루엔자 사례에서 입증했듯이 COVID-19 발병 위험과 전염병 중증도를 완화하기위한 예방 목적으로 제안 될 수 있으며, 인플루엔자와 인플루엔자 유사 질병, 특히 노인과 만성 질환을 앓고 있는 개인의 경우 이러한 종류의 질병에 걸리기 쉽고 심각도를 증가시킵니다. 

In particular, the oral administration of NAC, at the dose of 600 mg twice daily, may be proposed for preventive purposes aimed at attenuating the risk of developing COVID‐19 and its severity during epidemic periods, as we previously demonstrated in the case of influenza and influenza‐like illnesses,47 especially in elderly people and in individuals who suffer from chronic conditions that predispose them to this kind of diseases and increase their severity.

 

스마트 폰 접촉 추적 앱을 통해 탐지된 사람을 포함하여 감염된 SARS‐CoV‐2 보균자 근처에 있었던 사람은 COVID‐19 발병 위험을 줄이기 위해 경구 NAC를 복용하는 추가 대상이 될 수 있습니다.
 Persons who have been in proximity of infected SARS‐CoV‐2 carriers, including those detected by means of smartphone contact tracing apps, may be an additional target for taking oral NAC in order to decrease the risk of developing COVID‐19.

 

 

In addition, NAC has been shown to exert protective mechanisms against a variety of conditions associated with COVID‐19 and co‐morbidities thereof, also including cardiovascular diseases.16 

또한 NAC는 심혈관 질환 등 COVID-19 및 이의 동반 이환율과 관련된 다양한 질병에 대해 보호 메커니즘을 발휘하는 것으로 나타났습니다. 

 

Given that cardiac injury and thrombosis are well established as potentially lethal complications in COVID‐19, it is noteworthy that intravenously administered NAC has been shown to potentiate the vasodilator, anti‐inflammatory and antiaggregatory effects of nitroglycerin, and this useful interaction has been translated into improving outcomes, such as in acute myocardial infarction, unstable angina and acute pulmonary edema.68, 69 

정맥으로 투여된 NAC는 니트로 글리세린의 혈관 확장제, 항 염증 및 항 응집 효과를 강화하는 것으로 나타 났으며, 이 유용한 상호 작용은 급성 심근 경색, 불안정 협심증 및 급성 폐부종과 같은 결과를 개선하는 것으로 해석되었습니다.

 

Administration of NAC has been included among the possible strategies aimed at preserving endothelial function and limiting microthrombosis in severe forms of COVID‐19.70

NAC 투여는 심각한 형태의 COVID‐19.70에서 내피 기능을 보존하고 미세 혈전증을 제한하기위한 가능한 전략에 포함되었습니다.

Clearly, the potential anti‐COVID‐19 mechanisms and properties of this thiol have to be substantiated in controlled clinical trials, some of which are now in progress.12, 72

분명히 이 thiol의 잠재적 항-COVID-19 메커니즘 및 특성 통제된 임상시험에서 입증되어야 하며, 그중 일부는 현재 진행 중입니다.

 

In case of severe COVID‐19 forms with pulmonary and/or systemic symptoms, intravenously administered NAC at the high doses that are commonly used in case of paracetamol intoxication, given at the first onset of chest symptoms, would be expected to play an adjuvant therapeutic role in combination with antivirals or other drugs.

폐 및/또는 전신 증상이 있는 중증 COVID‐19 형태의 경우, 흉부 증상이 처음 발병할 때 투여되는 파라세타몰 중독의 경우 일반적으로 사용되는 고용량의 NAC를 정맥 주사하면, 항바이러스제 또는 기타 약물과 함께 사용되는 보조 역할을 할 것으로 예상됩니다. 

 

 

remdesivir와 같은 SARS-CoV-2에 대한 후보 항바이러스 치료제와 함께 NAC 및 구리의 잠재적 역할은 체계적 문헌 검색을 기반으로 가정되었습니다.

A potential role of NAC and copper in combination with candidate antiviral treatments against SARS‐CoV‐2, such as remdesivir, has been hypothesized based on a systematic literature search.71

CONFLICT OF INTEREST

The authors declare no conflicts of interest to disclose.

AUTHOR CONTRIBUTIONS

S. De Flora conceived and researched the hypothesis proposed in this manuscript and wrote the manuscript. R. Balansky and S. La Maestra critically reviewed the manuscript and contributed to the hypothesis exploration. All authors read and approved the published version of the manuscript.