염증 반사 inflammatory reflex. 한의학 역사를 바꿀 기념비적인 논문 2002년 nature !!

[문형철]

한의사의 전침으로

전신질환(전신 염증)을 치료할 수 있다

그 근거에 관한 네이처 논문!!!

https://www.youtube.com/watch?v=-891NuAX1Yo

https://www.youtube.com/watch?v=uqd7FGDA6AY

Abstract

Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.

“The mind has great influence over the body, and maladies often have their origin there.” Molière (1622–1673).

초록

염증은

미생물 침입이나 손상에 대한 국소적 보호 반응이다.

염증 반응의 결핍이나 과잉은

질병을 유발하고 수명을 단축시키므로 정밀하게 조절되어야 한다.

It must be fine-tuned and regulated precisely,

because deficiencies or excesses of the inflammatory response

cause morbidity and shorten lifespan.

콜린성 뉴런이 급성 염증을 억제한다는 발견은

신경계가 면역 반응을 조절하는 방식에 대한 우리의 이해를 질적으로 확장시켰다.

신경계는

심박수 및 기타 생명 기능을 제어하듯

염증 반응을 실시간으로 반사적으로 조절한다.

이제 선택적이고 가역적인 ‘고정된’ 신경 시스템을 통해

이 통찰력을 염증 치료에 적용할 기회가 열렸다.

“마음은 몸에 큰 영향을 미치며, 질병은 종종 그곳에서 비롯된다.” 몰리에르 (1622–1673).

Survival is impossible without vigilant defence against attack and injury. The innate immune system continuously surveys the body for the presence of invaders. When it encounters an attack, it involuntarily sets in motion a discrete, localized inflammatory response to thwart most pathogenic threats. The magnitude of the inflammatory response is crucial: insufficient responses result in immunodeficiency, which can lead to infection and cancer; excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, Crohn’s disease, atherosclerosis, diabetes, Alzheimer’s disease, multiple sclerosis, and cerebral and myocardial ischaemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more dangerous than the original inciting stimulus. Homeostasis and health are restored when inflammation is limited by anti-inflammatory responses that are redundant, rapid, reversible, localized, adaptive to changes in input and integrated by the nervous system.

생존은 

공격과 손상에 대한 경계 태세 없이는 불가능하다. 

선천성 면역 체계는 

침입자의 존재 여부를 지속적으로 감시한다. 

공격을 감지하면 

대부분의 병원성 위협을 저지하기 위해 

자발적으로 국소적인 염증 반응을 일으킨다. 

염증 반응의 규모는 매우 중요하다: 

반응이 불충분하면 

면역결핍이 발생하여 감염과 암으로 이어질 수 있으며, 

과도한 반응은 

류마티스 관절염, 크론병, 동맥경화증, 당뇨병, 알츠하이머병, 다발성 경화증,

 뇌 및 심근 허혈과 같은 질환에서 사망률을 높인다. 

패혈성 쇼크 증후군, 패혈증, 수막염, 중증 외상 등에서처럼 

염증이 혈류로 확산되면, 

염증 반응 자체가 초기 유발 자극보다 더 위험해질 수 있습니다. 

Homeostasis and health are restored

when inflammation is limited by anti-inflammatory responses

that are redundant, rapid, reversible, localized, adaptive to changes in

input and integrated by the nervous system.

염증이 중복적이고 신속하며 가역적이며 국소적이며 

입력 변화에 적응하고 

신경계에 의해 통합되는 항염증 반응에 의해 제한될 때, 

항상성과 건강이 회복됩니다.

The nervous system is composed of sensory systems (which detect the state of the body and organs) and motor systems (which transmit signals to the body and organs). Whereas the somatic motor system controls voluntary movements, the autonomic motor system controls visceral body functions and innervates glands (involuntary). The autonomic nervous system has two principal divisions, the parasympathetic pathway and the sympathetic pathway, which act either in synergy or in opposition to mediate basic physiological responses in real time. The autonomic system continuously controls heart rate and blood pressure, respiratory rate, gastrointestinal motility, body temperature and other constantly changing, essential life functions. The autonomic nervous system interacts with the primitive brain, including the limbic system (serving important memory functions), brain stem and hypothalamus. Hypothalamic neural output is relayed to sympathetic and parasympathetic nuclei in the brain stem and spinal cord. Hormonal input also controls the release of pituitary hormones, which in turn regulate basic functions of the endocrine organs. Autonomic nervous functions are normally subconscious, but essential basic autonomic functions can be placed under conscious control from signals originating in the higher brain (cerebral cortex). For example, subjects can be trained through biofeedback to decrease their heart rate by increasing parasympathetic outflow.

신경계는 

감각계(신체 및 장기 상태 감지)와 운동계(신체 및 장기로 신호 전달)로 구성된다. 

체성 운동계가 의지적 운동을 제어하는 반면, 

자율 운동계는 내장 기관 기능을 제어하고 

샘(비자발적)에 신경 분포를 제공한다. 

자율신경계는 두 가지 주요 분지인 

부교감 신경 경로와 교감 신경 경로로 나뉘며, 

이들은 시너지 또는 대립 작용을 통해 실시간으로 기본 생리적 반응을 조절한다. 

자율신경계는 

심박수와 혈압, 호흡수, 위장관 운동성, 체온 및 기타 지속적으로 변화하는 

필수 생명 기능을 지속적으로 제어한다. 

자율신경계는 

변연계(중요한 기억 기능을 담당), 뇌간, 시상하부를 포함한 원시 뇌와 상호작용한다. 

시상하부의 신경 출력은 

뇌간과 척수의 교감 및 부교감 신경핵으로 전달된다. 

호르몬 입력은 또한 뇌하수체 호르몬 분비를 조절하며, 

이는 다시 내분비 기관의 기본 기능을 조절한다. 

자율신경 기능은 일반적으로 무의식적이지만, 

고등 뇌(대뇌 피질)에서 발생하는 신호를 통해 

필수적인 기본 자율 기능을 의식적으로 제어할 수 있습니다.

 예를 들어, 

생체 피드백 훈련을 통해 부교감 신경 유출을 증가시켜 

심박수를 낮출 수 있습니다.

Recent insights have identified a basic neural pathway that reflexively monitors and adjusts the inflammatory response. Inflammatory stimuli activate sensory pathways that relay information to the hypothalamus. Like a knee-jerk reflex, in which the stretching of a patellar tendon elicits a rapidly opposing motor action, inflammatory input activates an anti-inflammatory response that is fast and subconscious. This prevents spillage of inflammatory products into the circulation. The nervous system integrates the inflammatory response: it gathers information about invasive events from several local sites, mobilizes defences and creates memory to improve chances for survival. Here I review evidence showing that the neural control of acute inflammation is reflexive, directly interconnected and controllable. Special emphasis is placed on cholinergic antiinflammatory mechanisms that inhibit the activation of macrophages and the release of cytokines (Fig. 1). I also discuss evidence indicating that stimulation of the vagus nerve, by either electrical or pharmacological means, prevents inflammation and inhibits the release of cytokines that are clinically relevant drug targets for treating inflammatory disease.

최근 연구 결과는 

염증 반응을 반사적으로 모니터링하고 조절하는 

기본 신경 경로를 확인했습니다. 

염증 자극은 

정보를 시상하부에 전달하는 감각 경로를 활성화합니다. 

슬개건 신장에 의한 반사적 운동 반응과 마찬가지로, 

염증 자극은 빠르고 무의식적인 항염증 반응을 활성화한다. 

이는 염증성 물질이 

순환계로 유출되는 것을 방지한다. 

신경계는 염

증 반응을 통합한다: 

여러 국소 부위에서 침습적 사건에 대한 정보를 수집하고, 

방어 기전을 동원하며, 

생존 가능성을 높이기 위한 기억을 생성한다. 

본고에서는 

급성 염증의 신경 조절이 반사적이며 직접적으로 상호 연결되고 

통제 가능하다는 증거를 검토한다. 

특히 

대식세포 활성화와 사이토카인 방출을 억제하는 

콜린성 항염증 기전에 중점을 둔다(그림 1).

 또한 미주신경 자극(전기적 또는 약리학적 방법)이 염증을 예방하고 

염증성 질환 치료의 임상적 표적이 되는 

사이토카인 방출을 억제한다는 증거를 논의한다.

Inflammation mediated by TNF

Tumour-necrosis factor (TNF), a cytokine with a relative molecular mass of 17,000 (Mr 17K), is produced by activated macrophages in response to pathogens and other injurious stimuli, and is a necessary and sufficient mediator of local and systemic inflammation1,2. Local increases in TNF cause the cardinal clinical signs of inflammation, including heat, swelling, pain and redness. Systemic increases in TNF mediate tissue injury by depressing cardiac output, inducing microvascular thrombosis and mediating systemic capillary leakage syndrome. TNF amplifies and prolongs the inflammatory response by activating other cells to release both cytokines such as interleukin 1 (IL-1) and high mobility group B1 (HMGB1), and mediators such as eicosanoids, nitric oxide and reactive oxygen species, which promote further inflammation and tissue injury3 . TNF is essential for the complete expression‎ of inflammation during invasion, and self-limited inflammation is normally characterized by decreasing TNF activity.

TNF에 의해 매개되는 염증 

종양괴사인자(TNF)는 

상대 분자량 17,000(Mr 17K)의 사이토카인으로, 

병원체 및 기타 손상 자극에 반응하여 활성화된 대식세포에 의해 생성되며, 

국소 및 전신 염증의 필요충분 매개체이다1,2. 

TNF의 국소적 증가는 

열감, 부종, 통증, 발적 등 염증의 주요 임상 증상을 유발한다. 

TNF의 전신적 증가는 

심박출량 저하, 미세혈관 혈전증 유발, 전신 모세혈관 누출 증후군 매개 등을 통해 

조직 손상을 매개한다. 

TNF는 

인터루킨 1(IL-1) 및 고이동성 그룹 B1(HMGB1)과 같은 사이토카인과 

에이코사노이드, 

산화질소, 활성산소종과 같은 매개체를 방출하도록 

다른 세포를 활성화함으로써 염증 반응을 증폭 및 연장시킵니다. 

이러한 물질들은 

추가적인 염증과 조직 손상을 촉진합니다³ . 

TNF는 

침습 과정 중 염증의 완전한 발현에 필수적이며, 

자가제한성 염증은 일반적으로 TNF 활성 감소로 특징지어집니다.

Low amounts of TNF can contribute to host defence by limiting the spread of pathogenic organisms into the circulation, promoting coagulation to localize the invader, and stimulating the growth of damaged tissues4 . In a typical ‘successful’ inflammatory response, the duration and magnitude of TNF release is limited, its beneficial and protective activities predominate, and it is not released systemically. Studies of the inflammatory action of TNF in non-malignant disease have led to widespread investigation of both the ‘normal’ mechanisms that regulate inflammation and the therapeutic potential of monoclonal antibodies specific for TNF.

소량의 TNF는 병원성 미생물의 순환계 확산을 제한하고, 

침입자를 국소화하기 위한 응고를 촉진하며, 

손상된 조직의 성장을 자극함으로써 숙주 방어에 기여할 수 있습니다⁴. 

전형적인 ‘성공적인’ 염증 반응에서는 

TNF 방출의 지속 시간과 규모가 제한되며, 

그 유익하고 보호적인 작용이 우세하고 전신적으로 방출되지 않습니다. 

비악성 질환에서 TNF의 염증 작용에 대한 연구는 

염증을 조절하는 ‘정상적인’ 메커니즘과 TNF 특이적 단일클론 항체의 치료적 잠재력에 대한 

광범위한 연구로 이어졌습니다.

Monoclonal antibodies against TNF

Early studies using monoclonal antibodies against TNF showed that this approach effectively prevents lethal tissue injury during bacterial invasion1 . Subsequent clinical trials led to the registration of both monoclonal antibodies against TNF, and TNF-binding proteins for treating rheumatoid arthritis and Crohn’s disease. Many individuals with these debilitating inflammatory illnesses have enjoyed disease remissions and an improved quality of life. Crippling joint pain has been alleviated in children with rheumatoid arthritis treated with TNF antibodies; some of the youngest patients have even experienced ‘catch-up growth’ and normalization of development (U. Andersson, personal communication). These and other clinical successes with TNF monoclonal antibodies have proved that cytokine responses can be manipulated to specific therapeutic advantage for inflammatory disease.

TNF에 대한 단일클론 항체

TNF에 대한 단일클론 항체를 이용한 초기 연구는 이 접근법이 세균 침입 시 치명적인 조직 손상을 효과적으로 예방함을 보여주었다1. 이후 임상 시험을 통해 TNF에 대한 단일클론 항체와 TNF 결합 단백질 모두 류마티스 관절염 및 크론병 치료제로 등록되었다. 이러한 쇠약성 염증성 질환을 가진 많은 환자들이 질병 완화와 삶의 질 향상을 경험했다. TNF 항체로 치료받은 소아 류마티스 관절염 환자들의 심한 관절 통증이 완화되었으며, 일부 최연소 환자들은 '성장 회복'과 발달 정상화까지 경험했다(U. Andersson, 개인적 소통). TNF 단일클론 항체를 통한 이러한 임상적 성과들은 염증성 질환 치료를 위해 사이토카인 반응을 특정 치료적 이점으로 조작할 수 있음을 입증했다.

But strategies using TNF antibodies have not been translated successfully into treatments for bacterial invasion or sepsis, for reasons that have been reviewed extensively elsewhere5 . Most notably, serum concentrations of TNF were undetectable in most of the individuals recruited into clinical sepsis trials, because the study group comprised a heterogeneous population with diverse diseases at varying stages of illness. In early experiments of the use of TNF monoclonal antibodies in bacteraemia, it became clear that TNF is an early mediator of inflammation and that TNF antibodies are ineffective if therapy is initiated after serum TNF has been cleared1 . Continued interest in understanding the use of TNF antibodies for individuals with sepsis is now focused on identifying a homogenous study population with increased serum TNF for treatment early in the course of illness.

그러나 TNF 항체를 활용한 전략은 세균 침입이나 패혈증 치료로 성공적으로 전환되지 못했는데, 그 이유는 다른 곳에서 광범위하게 검토된 바 있다⁵. 특히, 임상 패혈증 시험에 모집된 대부분의 개인에서 혈청 내 TNF 농도는 검출 불가능한 수준이었다. 이는 연구 집단이 다양한 질환을 가진 이질적인 인구로 구성되었으며, 각자의 질병 단계도 상이했기 때문이다. 균혈증에 TNF 단일클론 항체를 사용한 초기 실험에서, TNF가 염증의 초기 매개체이며 혈청 내 TNF가 제거된 후 치료를 시작하면 TNF 항체가 효과가 없다는 점이 분명해졌다¹. 패혈증 환자에게 TNF 항체를 사용하는 방법을 이해하려는 지속적인 관심은 현재 질병 초기 단계에서 치료를 위해 혈청 TNF가 증가된 동질적인 연구 집단을 식별하는 데 집중되고 있다.

An alternative therapeutic strategy is to target ‘late’ mediators of lethality that are produced after TNF in the inflammatory pathway3 . HMGB1 has been implicated as an experimental therapeutic target that is produced relatively late in the course of endotoxaemia3,6. Antibodies specific for HMGB1 confer significant protection against the lethality of endotoxaemia, even when the first antibody doses are administered after the early TNF concentrations have been cleared. Reducing serum concentrations of HMGB1 by administering ethyl pyruvate as late as 24 h after the onset of sepsis rescues animals from lethality, indicating that it may now be possible to develop therapies for sepsis that cover a significantly wider, clinically relevant treatment window7,8.

대안적 치료 전략은 염증 경로에서 TNF 이후 생성되는 ‘후기’ 치사성 매개체를 표적으로 삼는 것이다³ . HMGB1은 내독소혈증 진행 과정에서 상대적으로 늦게 생성되는 실험적 치료 표적으로 제시되었다³⁶. HMGB1 특이적 항체는 초기 TNF 농도가 제거된 후 첫 항체 투여가 이루어지더라도 내독소혈증의 치사성에 대해 상당한 보호 효과를 제공한다. 패혈증 발병 후 24시간이 지난 시점에서도 에틸 피루베이트를 투여하여 혈청 내 HMGB1 농도를 감소시키면 동물들을 치명적 결과로부터 구할 수 있으며, 이는 이제 임상적으로 의미 있는 훨씬 더 넓은 치료 창을 포괄하는 패혈증 치료법을 개발할 수 있음을 시사한다⁷,⁸.

Other cytokines have been implicated as therapeutic targets in the pathogenesis of inflammatory diseases, and it is likely that future treatment plans will target mediators in addition to TNF. Although I focus the discussion of neural regulation of inflammation primarily on cholinergic inhibition of TNF, evidence indicates that these neural anti-inflammatory mechanisms also inhibit the release of IL-1, IL-18 and HMGB1.

다른 사이토카인들도 염증성 질환의 병리 기전에서 치료 표적으로 제시되어 왔으며, 향후 치료 계획은 TNF 외에도 다른 매개체들을 표적으로 삼을 가능성이 높다. 비록 본 논의에서 염증의 신경 조절에 대해 주로 TNF의 콜린성 억제에 초점을 맞추고 있지만, 이러한 신경성 항염증 기전들이 IL-1, IL-18 및 HMGB1의 방출도 억제한다는 증거가 제시되고 있다.

Anti-inflammatory responses normally inhibit inflammation

Highly conserved, counter-regulatory mechanisms normally limit the acute inflammatory response and prevent the spread of inflammatory mediators into the bloodstream (Table 1). Activated immunologically competent cells release TNF receptor fragments that bind and neutralize its inflammatory and potentially toxic actions9 . Anti-inflammatory cytokines, such as IL-10 and transforming growth factor-b (TGF-b), specifically inhibit the release of TNF and other proinflammatory mediators10. Adrenal glucocorticoids, adrenaline, a-melanocyte-stimulating hormone (a-MSH) and other ‘classical’ stress hormones inhibit cytokine synthesis and intracellular signal transduction11–14. Spermine accumulates at sites of tissue injury and infection and inhibits macrophage activation and cytokine synthesis15.

항염증 반응은 일반적으로 염증을 억제한다

고도로 보존된 상쇄 조절 기전은

일반적으로 급성 염증 반응을 제한하고

염증 매개체의 혈류 확산을 방지한다(표 1).

활성화된 면역능 세포는

TNF 수용체 단편을 방출하여 염증 및 잠재적 독성 작용을 결합 및 중화시킨다9.

IL-10 및 변형성장인자-β(TGF-β)와 같은 항염증성 사이토카인은

TNF 및 기타 전염증성 매개체의 방출을

특이적으로 억제한다10.

부신 글루코코르티코이드, 아드레날린, α-멜라노사이트 자극 호르몬(α-MSH) 및

기타 ‘전통적’ 스트레스 호르몬은 사이토카인 합성과

세포 내 신호 전달을 억제한다¹¹⁻¹⁴.

스퍼민은

조직 손상 및 감염 부위에 축적되어

대식세포 활성화와 사이토카인 합성을 억제한다¹⁵.

The importance of these endogenous anti-inflammatory pathways has been shown by experimentally impairing isolated pathways. For example, animals subjected to hypophysectomy or adrenalectomy are significantly sensitized to the lethal effects of endotoxin16. In the absence of an adequate adrenocorticotropic hormone (ACTH) and glucocorticoid response, TNF is significantly overexpressed during endotoxaemia16–18. Functional deficiencies in the release of corticotropin-releasing factor (CRF) predispose Lewis rats to developing experimental arthritis induced by streptococcal antigens because of an insufficient glucocorticoid response13,19,20. Animals deficient in IL-10 develop a chronic inflammatory bowel disease that predominately affects the colon21 and are susceptible to a more severe form of collagen-induced arthritis22. Administration of specific pharmacological spermine antagonists significantly increases local TNF activity and carrageenan-induced oedema formation, and amplifies the inflammatory response15. Together, these findings show that loss of endogenous anti-inflammatory mechanisms converts a normally protective, self-limited inflammatory response into an excessive, potentially deleterious response.

이러한 내인성 항염증 경로의 중요성은 

특정 경로를 실험적으로 손상시켜 입증되었다. 

예를 들어, 

뇌하수체 절제술 또는 부신 절제술을 받은 동물은 

내독소의 치명적 효과에 대해 현저히 민감해진다¹⁶. 

적절한 부신피질조절호르몬(ACTH) 및 글루코코르티코이드 반응이 결여된 상태에서는 

내독소혈증 동안 TNF가 현저히 과발현된다¹⁶⁻¹⁸. 

코르티코트로핀 방출 인자(CRF) 분비의 기능적 결핍은 

글루코코르티코이드 반응이 불충분하여 

루이스 쥐가 연쇄상구균 항원에 의해 유발된 실험적 관절염에 걸리기 쉽게 만든다13,19,20. 

IL-10 결핍 동물은 

주로 결장에 영향을 미치는 만성 염증성 장 질환을 발병하며21, 

더 심각한 형태의 콜라겐 유발 관절염에 취약하다22. 

특이적 약리학적 스퍼민 길항제 투여는 

국소 TNF 활성과 카라기난 유발 부종 형성을 현저히 증가시키고 

염증 반응을 증폭시킵니다15. 

종합하면, 

이러한 결과들은 내인성 항염증 

기전의 상실이 정상적으로 보호적이고 

자가 제한적인 염증 반응을 과도하고 잠재적으로 유해한 반응으로 

전환시킴을 보여줍니다.

Communication between immune and nervous systems

The activation of pituitary-dependent adrenal responses after endotoxin administration23 provided early evidence that inflammatory stimuli can activate anti-inflammatory signals from the central nervous system (CNS). Subsequently, Besedovsky et al.24 showed directly that inflammation in peripheral tissues alters neuronal signalling in the hypothalamus. Extensive work has identified a common molecular basis for communication, with cells from each system expressing signalling ligands and receptors from the other25. For example, neurons in the CNS can synthesize and express TNF and IL-1, and these cytokines may participate in neuronal communication26,27. This communication is bi-directional, because cytokines can activate hypothalamic-pituitary release of glucocorticoids and, in turn, glucocorticoids suppress further cytokine synthesis28. In addition, cells of the immune system can produce neuropeptides (including endorphins), acetylcholine and other neurotransmitters.

The importance of the interaction between the nervous system and immune system signalling has been demonstrated recently in the development of pathological pain. Watkins and Maier29 have proposed that cytokines produced by inflammatory and glial cells change neuronal excitability and that this link contributes directly to the development of intractable pain.

면역계와 신경계 간의 소통

내독소 투여 후 뇌하수체 의존성 부신 반응의 활성화23은 

염증 자극이 중추신경계(CNS)로부터 항염증 신호를 활성화할 수 있다는 

초기 증거를 제공했다. 

이후 Besedovsky 등24은 

말초 조직의 염증이 시상하부의 신경 신호 전달을 변화시킨다는 점을 직접 입증했다. 

광범위한 연구를 통해 

양측 시스템 간 소통의 공통 분자적 기반이 확인되었으며, 

각 시스템의 세포가 상대방의 신호 전달 리간드와 수용체를 발현한다는 사실이 밝혀졌다25. 

예를 들어, 

중추신경계의 뉴런은 TNF와 IL-1을 합성 및 발현할 수 있으며, 

이러한 사이토카인은 신경세포 간 소통에 관여할 수 있다26,27. 

이러한 소통은 양방향적입니다. 

사이토카인이 시상하부-뇌하수체에서 글루코코르티코이드 분비를 활성화할 수 있으며, 

반대로 글루코코르티코이드가 추가적인 사이토카인 합성을 억제하기 때문입니다²⁸. 

또한 면역계 세포는 

신경펩타이드(엔도르핀 포함), 아세틸콜린 및 기타 신경전달물질을 생성할 수 있습니다.

신경계와 면역계 신호 전달 간의 상호작용 중요성은 

최근 병리적 통증 발생 과정에서 입증되었다. 

왓킨스와 마이어²⁹는 

염증 세포 및 신경교세포가 생성하는 사이토카인이 신경 세포의 흥분성을 변화시키며, 

이러한 연결이 난치성 통증 발생에 직접 기여한다고 제안하였다.

Cholinergic anti-inflammatory pathway

Our understanding of the basic mechanisms that regulate inflammation has been advanced by the identification of a neural mechanism that inhibits macrophage activation through parasympathetic outflow30. Called the ‘cholinergic anti-inflammatory deactivated (Fig. 1). The vagus nerve (which was named for its wandering course) innervates the principal organs, including those that contain the reticuloendothelial system (liver, lung, spleen, kidneys and gut)31. Experimental activation of the cholinergic anti-inflammatory pathway by direct electrical stimulation of the efferent vagus nerve inhibits the synthesis of TNF in liver, spleen and heart, and attenuates serum concentrations of TNF during endotoxaemia30,32. Vagotomy significantly exacerbates TNF responses to inflammatory stimuli and sensitizes animals to the lethal effects of endotoxin.

콜린성 항염증 경로

교감신경 유출을 통해 

대식세포 활성화를 억제하는 신경 기전의 규명을 통해 염증을 조절하는 

기본 메커니즘에 대한 이해가 진전되었다³⁰. 

이를 ‘콜린성 항염증 비활성화(DAI)’ 경로라 명명하였다(그림 1). 

미주신경(그 경로가 방황하는 듯한 모양새를 닮아 명명됨)은 

망상내피계(liver, lung, spleen, kidneys and gut)를 포함하는 

주요 기관들을 신경 분포한다31. 

미주 신경의 원심성 경로를 직접 전기 자극하여 

콜린성 항염증 경로를 실험적으로 활성화하면 

간, 비장, 심장에서 TNF 합성이 억제되고 

내독소혈증 시 혈청 내 TNF 농도가 감소한다³⁰,³². 

미주 신경 절제술은 

염증 자극에 대한 TNF 반응을 현저히 악화시키고 

내독소의 치명적 효과에 대한 동물의 감수성을 증가시킨다.

This ‘hard-wired’ connection between the nervous and immune systems functions as an anti-inflammatory mechanism in other models of systemic and local inflammation. Direct stimulation of the vagus nerve in situ inhibits proinflammatory cytokine synthesis in liver and cardiac tissue obtained from animals subjected to ischaemia-reperfusion by transient aortic clamping. Stimulation of either the right or the left cervical vagus nerves protects against the development of hypotension and inhibits serum TNF responses to ischaemia reperfusion32. The protection conferred by stimulation of the vagus nerve is dependent on the applied voltage and is associated with normalization of tachycardia during the reperfusion-induced hypotensive phase32. In a standardized model of experimental murine arthritis induced by the application of carrageenan, vagus nerve stimulation inhibits the inflammatory response and suppresses the development of paw swelling, indicating that the cholinergic anti-inflammatory pathway can inhibit localized inflammation specifically33 pathway’ because acetylcholine is the principle parasympathetic neurotransmitter, macrophages that are exposed to acetylcholine are effectively33.

신경계와 면역계 사이의 이러한 '고정된 연결'은 

전신 및 국소 염증의 다른 모델에서도 항염증 기전으로 기능한다. 

현장에서 미주신경을 직접 자극하면, 

일시적 대동맥 결찰로 허혈-재관류 처리를 받은 동물에서 채취한 

간 및 심장 조직에서 전염증성 사이토카인 합성을 억제한다. 

우측 또는 좌측 경부 미주신경의 자극은 

저혈압 발생을 방지하고 

허혈-재관류에 대한 혈청 TNF 반응을 억제한다³². 

미주신경 자극에 의한 보호 효과는 

가해진 전압에 의존하며, 재관류 유발 저혈압 단계 동안 빈맥의 정상화와 연관된다³². 

카라기난 적용으로 유도된 표준화된 실험적 쥐 관절염 모델에서, 

미주신경 자극은 염증 반응을 억제하고

 발 부종 발생을 억제하여 콜린성 항염증 경로가 국소 염증을 특이적으로 억제할 수 있음을 시사한다³³. 

아세틸콜린이 

주요 부교감 신경전달물질이기 때문에, 

아세틸콜린에 노출된 대식세포는

 효과적으로³³ '경로'를 억제한다.

The molecular dovetail between the cholinergic nervous system and the innate immune system is a nicotinic, a-bungarotoxinsensitive macrophage acetylcholine receptor30. Exposure of human macrophages, but not peripheral blood monocytes, to nicotine or acetylcholine inhibits the release of TNF, IL-1 and IL-18 in response to endotoxin. Tissue macrophages, but not circulating monocytes, produce most of the TNF that appears systemically during an excessive inflammatory response. Interaction between the macrophage cholinergic receptor and its ligand inhibits the synthesis of proinflammatory cytokines (TNF, IL-1 and IL-18) but not anti-inflammatory cytokines (such as IL-10)30. Acetylcholine inhibits the expression‎ of TNF protein in macrophages, but not the induction of TNF messenger RNA levels, indicating that activation of the cholinergic receptor transduces intracellular signals that inhibit cytokine synthesis at a post-transcriptional stage.

콜린성 신경계와 선천성 면역계 사이의 분자적 연결 고리는 

니코틴성, a-붕가독소 민감성 대식세포 아세틸콜린 수용체이다³⁰. 

말초 혈액 단핵구는 아니지만, 

인간 대식세포를 니코틴이나 아세틸콜린에 노출시키면 

내독소에 대한 반응으로 TNF, IL-1 및 IL-18의 방출이 억제된다. 

조직 대식세포는 순환 단핵구와는 달리

 과도한 염증 반응 시 체내에 나타나는 TNF의 대부분을 생성한다. 

대식세포 콜린성 수용체와 그 리간드 간의 상호작용은 

전염증성 사이토카인(TNF, IL-1 및 IL-18)의 합성을 억제하지만, 

항염증성 사이토카인(예: IL-10)의 합성은 억제하지 않는다³⁰. 

아세틸콜린은 대식세포에서 TNF 단백질 발현을 억제하지만, 

TNF 메신저 RNA 수준 유도는 억제하지 않아, 

콜린성 수용체 활성화가 전사 후 단계에서 

사이토카인 합성을 억제하는 세포 내 신호를 전달함을 시사한다.

As compared with macrophages, monocytes are refractory to the cytokine-inhibiting effects of acetylcholine: only supraphysiological concentrations of cholinergic agonists inhibit cytokine synthesis in monocytes30. The macrophage acetylcholine receptor is distinct from the muscarinic receptor activities identified on lymphocytes, peripheral blood mononuclear cells and alveolar macrophages34,35. The exquisite sensitivity of macrophages to acetylcholine suggests that other non-neuronal cells that produce acetylcholine (such as epithelial cells, T lymphocytes and endothelial cells) might also participate in modulating the function of adjacent tissue macrophages36,37

대식세포에 비해 단핵구는 

아세틸콜린의 사이토카인 억제 효과에 내성이 있습니다: 

생리학적 농도를 초과하는 콜린성 작용제만이 

단핵구에서 사이토카인 합성을 억제합니다30. 

대식세포의 아세틸콜린 수용체는

 림프구, 말초혈 단핵구 및 폐포 대식세포에서 확인된 

무스카린성 수용체 활성과는 구별됩니다34,35. 

대식세포가 아세틸콜린에 대해 보이는 매우 높은 민감도는 

아세틸콜린을 생성하는 다른 비신경 세포(예: 상피세포, T 림프구 및 내피세포) 역시 

인접 조직 대식세포의 기능 조절에 관여할 수 있음을 시사합니다36,37.

Vagus nerve stimulation suppresses inflammation

Stimulation of efferent vagus nerve activity has been associated classically with slowing heart rate, induction of gastric motility, dilation of arterioles and constriction of pupils. Inhibition of the inflammatory response can now be added to this list (Fig. 1). From an oversimplified, teleological engineering perspective, there are many reasons why a neural-based anti-inflammatory pathway is advantageous. The diffusible anti-inflammatory network, which includes glucocorticoids, anti-inflammatory cytokines and other humoral mediators, is slow, distributed, non-integrated and dependent on concentration gradients. By contrast, the cholinergic anti-inflammatory pathway is discrete and localized in tissues where invasion and injury typically originate (Fig. 2).

미주신경 자극은 염증을 억제한다

미주신경 원심성 활동의 자극은 전통적으로 심박수 감소, 위 운동성 유도, 세동맥 확장 및 동공 수축과 연관되어 왔다. 이제 염증 반응 억제가 이 목록에 추가될 수 있다(그림 1). 지나치게 단순화된 목적론적 공학적 관점에서, 신경 기반 항염증 경로가 유리한 이유는 많다. 글루코코르티코이드, 항염증성 사이토카인 및 기타 체액성 매개체를 포함하는 확산성 항염증 네트워크는 느리고, 분산적이며, 비통합적이며 농도 구배에 의존한다. 반면 콜린성 항염증 경로는 침습과 손상이 일반적으로 발생하는 조직 내에서 분리되고 국소화된다(그림 2).

As compared with the routine, biological pace of a typical, diffusible inflammatory response (hours to days), neural signalling is like lightning. This regulatory attribute is highly advantageous for containing immune activation at the crucial stages of a nascent response. Neural control of biological functions is short-lived: after a brief refractory period, responding cells can resume function as required in the absence of further neural input. Recovery of immune function after transient inhibition enables necessary local inflammatory responses to be mobilized during persisting threat or infection. The impact of sensitization or desensitization developing after, respectively, denervation or repeated neural firing to an inflammatory site has not been explored, but it would be predicted to influence anti-inflammatory function.

전형적인 확산성 염증 반응의 생물학적 속도(수 시간에서 수일)와 비교할 때, 신경 신호 전달은 번개처럼 빠릅니다. 이러한 조절 특성은 초기 반응의 중요한 단계에서 면역 활성화를 억제하는 데 매우 유리합니다. 생물학적 기능에 대한 신경 조절은 단기적이다: 짧은 불응기 후, 반응 세포는 추가 신경 입력 없이 필요에 따라 기능을 재개할 수 있다. 일시적 억제 후 면역 기능의 회복은 지속적 위협이나 감염 시 필요한 국소 염증 반응을 동원할 수 있게 한다. 염증 부위에 대한 신경 절단 또는 반복적 신경 발화 후 각각 발생하는 감작 또는 탈감작의 영향은 아직 탐구되지 않았으나, 항염증 기능에 영향을 미칠 것으로 예측된다.

Neural regulation of discrete, distributed, localized inflammatory sites provides a mechanism for integrating responses in real time. It is intriguing to consider that, in addition to the development of immunological memory, the involvement of the cholinergic anti-inflammatory pathway might also modulate processing events that promote neural memory of the peri-inflammatory events (that is, the ‘hissing snake’ or ‘charging lion’ that caused the wound and/or infection). Clark et al.38 recently discovered that electrical stimulation of the vagus nerve in humans significantly enhanced word-recognition memory, indicating that memory formation and vagus nerve activity are closely linked.

분리되고 분산되며 국소화된 염증 부위에 대한 신경 조절은 실시간으로 반응을 통합하는 메커니즘을 제공한다. 면역학적 기억 형성과 더불어, 콜린성 항염증 경로의 관여가 염증 주변 사건(즉, 상처 및/또는 감염을 유발한 ‘쉭쉭거리는 뱀'이나 '돌진하는 사자’)에 대한 신경 기억을 촉진하는 처리 과정을 조절할 수도 있다는 점은 흥미롭다. Clark 등³⁸은 최근 인간의 미주신경 전기 자극이 단어 인식 기억을 현저히 향상시킨다는 사실을 발견하여, 기억 형성과 미주신경 활동이 밀접하게 연관되어 있음을 시사했다.

Sensory function of vagus nerve signals in inflammation

The CNS receives sensory input from the immune system through both humoral and neural routes. Blalock39,40originally suggested that the immune system functions as a ‘sixth sense’ that detects microbial invasion and produces molecules that relay this information to the brain. TNF and other immunological mediators can gain access to brain centres that are devoid of a blood–brain barrier in the circumventricular region. Indeed, the dorsal vagal complex, comprising the sensory nuclei of the solitary tract, the area postrema and the dorsal motor nucleus of the vagus, responds to increased circulating amounts of TNF by altering motor activity in the vagus nerve41–43. This humoral route for communication between the immune system and the nervous system has been implicated in the development of fever, anorexia, activation of hypothalamic-pituitary responses to infection and injury, and other behavioural manifestations of illness. Sensory innervation of immune organs by ascending fibres travelling in the vagus nerve, as well as by other pain and ascending sensory pathways, provides important input about the status of invasive and injurious challenges in distributed body compartments. Notably, these neural inflammation-sensing pathways can function at low thresholds of detection and can activate responses even when the inflammatory agents are present in tissues in quantities that are not high enough to reach the brain through the bloodstream. Watkins and colleagues44–47 have provided insight into the sensory role of afferent vagus nerve fibres by observing that vagotomy blunts the development of fever in animals exposed to intra-abdominal IL-1.

염증에서의 미주신경 신호 감각 기능

중추신경계(CNS)는 체액성 및 신경성 경로를 통해 면역계로부터 감각 입력을 받는다. Blalock³⁹,⁴⁰은 면역계가 미생물 침입을 감지하고 이 정보를 뇌로 전달하는 분자를 생성하는 '여섯 번째 감각'으로 기능한다고 최초 제안했다. TNF 및 기타 면역학적 매개체는 뇌실 주위 영역에서 혈액-뇌 장벽이 없는 뇌 중심부에 접근할 수 있다. 실제로, 고립 신경로의 감각핵, 포스트레마 영역 및 미주 신경의 등측 운동핵으로 구성된 등측 미주 복합체는 순환하는 TNF 양의 증가에 반응하여 미주 신경의 운동 활동을 변화시킵니다. 면역계와 신경계 간 이러한 체액성 소통 경로는 발열, 식욕부진, 감염 및 손상에 대한 시상하부-뇌하수체 반응 활성화, 기타 질병의 행동적 증상 발현과 연관되어 있습니다. 미주신경을 따라 상승하는 섬유 및 기타 통증·상승 감각 경로를 통한 면역 기관의 감각 신경 분포는 분산된 신체 구획 내 침습적·손상적 도전 요인의 상태에 대한 중요한 정보를 제공합니다. 특히, 이러한 신경성 염증 감지 경로는 낮은 감지 역치에서 기능할 수 있으며, 염증 유발 물질이 혈류를 통해 뇌에 도달하기에 충분하지 않은 양으로 조직에 존재할 때에도 반응을 활성화할 수 있다. 왓킨스(Watkins)와 동료들⁴⁴⁻⁴⁷은 복강 내 IL-1에 노출된 동물에서 미주신경 절제술이 발열 발생을 둔화시킨다는 관찰을 통해 구심성 미주신경 섬유의 감각적 역할에 대한 통찰을 제공하였다.

The afferent vagus pathway is activated by very low doses of endotoxin or IL-1; but higher doses of these agents can directly activate thermogenic responses through the humoral route to the brain48. It is not completely clear how the vagus nerve ‘detects’ the presence of low doses of endotoxin or other inflammatory agents, but neurons in the vagus nerve express IL-1 receptor mRNA and discrete IL-1-binding sites have been identified on glomus cells in the vagus nerve proper41,49.

Electrophysiological studies indicate that vagus nerve signals also can be activated by TNF, other cytokines, mechanoreceptors, chemoreceptors, temperature sensors and osmolarity sensors that might be activated at an inflammatory locus50. Somatic sensory input into the CNS is organized somatotopically, such that sensory input from a discrete peripheral site is localized precisely in the ascending fibre pathways and brain. The first CNS synapse for afferent vagus signals lies in the nucleus tractus solitarius, and electrolytic lesioning of this region impairs the development of IL-1-induced fever51. Thus, inflammation-derived sensory input can be processed differentially in the brain, depending on the location of the inflammatory site and the nature of the sensory signal.

구심성 미주 신경 경로는 매우 낮은 용량의 내독소 또는 IL-1에 의해 활성화되지만, 이러한 물질의 더 높은 용량은 체액 경로를 통해 뇌에 직접 열 생성 반응을 활성화할 수 있습니다48. 미주 신경이 저용량 내독소나 기타 염증 유발 물질의 존재를 어떻게 '감지'하는지는 완전히 명확하지 않으나, 미주 신경 내 뉴런은 IL-1 수용체 mRNA를 발현하며 미주 신경 본체의 글로무스 세포에서 분리된 IL-1 결합 부위가 확인되었다41,49.

전기생리학적 연구에 따르면 미주 신경 신호는 TNF, 기타 사이토카인, 기계수용체, 화학수용체, 온도 센서 및 삼투압 센서(이들 모두 염증 부위에서 활성화될 수 있음)에 의해서도 활성화될 수 있다50. 중추신경계(CNS)로의 체성 감각 입력은 체감도적(somatotopically)으로 조직되어 있어, 특정 말초 부위에서 오는 감각 입력이 상승 섬유 경로와 뇌에서 정확히 국소화된다. 구심성 미주 신호의 첫 중추신경계 시냅스는 고립로핵(nucleus tractus solitarius)에 위치하며, 이 부위의 전기적 병변은 IL-1 유발 발열의 발생을 저해한다51. 따라서 염증 유래 감각 입력은 염증 부위의 위치와 감각 신호의 특성에 따라 뇌에서 차별적으로 처리될 수 있다.

Reflex inhibition of inflammation

The inflammation-sensing and inflammation-suppressing functions outlined above provide the principal components of the inflammatory reflex (Fig. 3). The appearance of pathogenic organisms in a local wound, or at the site of epithelial barrier dysfunction, activates innate immune cells that release cytokines. These activate sensory fibres that ascend in the vagus nerve to synapse in the nucleus tractus solitarius. Increased efferent signals in the vagus nerve suppress peripheral cytokine release through macrophage nicotinic receptors and the cholinergic anti-inflammatory pathway. The ‘inflammatory reflex’ is described as localized, rapid and discrete; but it can also induce systemic humoral anti-inflammatory responses. This occurs because vagus nerve activity can be relayed to the medullary reticular formation, to the locus ceruleus and to the hypothalamus, leading to increased release of ACTH from the anterior pituitary.

염증의 반사적 억제

상기 설명된 염증 감지 및 억제 기능은 

염증 반사의 주요 구성 요소이다(그림 3). 

국소 상처나 상피 장벽 기능 장애 부위에 병원성 미생물이 출현하면 

선천성 면역 세포가 활성화되어 사이토카인을 분비한다. 

이로 인해 감각 섬유가 활성화되어 

미주신경을 따라 상승하여 

고립로핵에서 시냅스를 형성한다. 

미주 신경의 원심성 신호 증가는 

대식세포의 니코틴성 수용체와 콜린성 항염증 경로를 통해 

말초 사이토카인 방출을 억제한다.

 '염증 반사'는 

국소적이고 신속하며 분리된 것으로 묘사되지만, 

전신적 체액성 항염증 반응을 유도할 수도 있다. 

이는 미주 신경 활동이 

수질 망상 형성체, 청색핵 및 시상하부로 전달되어 

뇌하수체 전엽에서 ACTH 분비를 증가시키기 때문이다

Increased cytokine production in tissues causes pain, providing another mechanism for transferring information from the immune system to the brain. This information can be relayed to other brain centres that influence motor output in the vagus nerve. Pain and stress can activate the flight-or-fight responses, and the resultant increase of adrenaline and noradrenaline also can inhibit macrophage activation and suppress synthesis of TNF and other cytokines13,52,53. High sympathetic activity and resultant increases in catecholamines stimulate the b-adrenergic-receptor-dependent release of IL-10, a potent anti-inflammatory cytokine, from monocytes11,54. Thus, the anti-inflammatory effects of the sympathetic and parasympathetic nervous systems seem to be synergistic in this setting.

.

조직 내 사이토카인 생산 증가가 통증을 유발하며, 

이는 면역 체계에서 뇌로 정보를 전달하는

 또 다른 기전을 제공한다. 

이 정보는 미주 신경의 운동 출력에 영향을 미치는 

다른 뇌 중추로 전달될 수 있다. 

통증과 스트레스는 

도피-또는-투쟁 반응을 활성화할 수 있으며, 

그 결과 증가된 아드레날린과 노르아드레날린은 대식세포 활성화를 억제하고 

TNF 및 기타 사이토카인 합성을 억제할 수도 있다13,52,53. 

높은 교감 신경 활동과 그에 따른 카테콜아민 증가가 

단핵구로부터 강력한 항염증성 사이토카인인 IL-10의 b-아드레날린 수용체 의존적 방출을 자극한다11,54. 

따라서 

교감신경계와 부교감신경계의 항염증 효과는 

이 상황에서 시너지 효과를 발휘하는 것으로 보인다.

Classical teaching stresses that actions of the sympathetic and parasympathetic nervous systems are usually in opposition. But in many situations the two systems function synergistically. For example, simultaneous stimulation of both sympathetic and vagus nerves produces a higher increase in cardiac output than does isolated stimulation of either nerve alone55. Flight-or-fight activation of sympathetic responses also stimulates increased vagus nerve output. The combined action of these neural systems is significantly antiinflammatory and is positioned anatomically to constrain local inflammation by preventing spillover of potentially lethal toxins into the circulation through both local (neural) and systemic (humoral) anti-inflammatory mechanisms.

전통적인 교과 과정은 

교감신경계와 부교감신경계의 작용이 일반적으로 상반된다고 강조한다. 

그러나 

많은 상황에서 두 시스템은 시너지적으로 기능한다. 

예를 들어, 교감신경과 미주신경을 동시에 자극하면 어느 한 신경만 단독으로 자극할 때보다 심박출량이 더 크게 증가한다55. 교감 반응의 도피-또는-투쟁 활성화는 또한 미주 신경 출력을 증가시킵니다. 이러한 신경계의 복합 작용은 상당한 항염증 효과를 가지며, 국소적(신경적) 및 전신적(체액적) 항염증 기전을 통해 잠재적으로 치명적인 독소가 순환계로 유출되는 것을 방지함으로써 국소 염증을 억제할 수 있는 해부학적 위치에 있습니다.

Implications of the inflammatory reflex

Knowledge of the inflammatory reflex and the cholinergic antiinflammatory pathway is yielding insight into both physiological pathways and therapeutic strategies (Fig. 4). For example, it may be possible to activate neural anti-inflammatory mechanisms using small molecules that initiate signals in proximal components of the pathway in the CNS. One such molecule is CNI-1493, a tetravalent guanylhydrazone that was originally described as an inhibitor of macrophage activation and TNF release56,57.

염증 반사의 함의

염증 반사와 콜린성 항염증 경로에 대한 지식은 생리학적 경로와 치료 전략 모두에 대한 통찰력을 제공하고 있다(그림 4). 예를 들어, 중추신경계(CNS) 내 경로의 근위부 구성 요소에서 신호를 시작하는 소분자를 사용하여 신경성 항염증 기전을 활성화할 수 있을 것이다. 그러한 분자 중 하나는 CNI-1493으로, 원래 대식세포 활성화 및 TNF 방출 억제제로 기술된 4가 구아닐히드라존이다⁵⁶,⁵⁷.

CNI-1493 inhibits TNF synthesis and inflammatory responses in animal models of local and systemic inflammation58. It also significantly reduced disease severity in a small clinical trial of severe Crohn’s disease and is currently being eval‎uated in a large phase II trial of Crohn’s disease59. Unexpectedly, recent evidence has shown that the TNF-suppressing activities of CNI-1493 in vivo are dependent on the cholinergic anti-inflammatory pathway, and that CNI1493 functions as a pharmacological stimulator of the vagus nerve32,60: intracerebral application of small doses of CNI-1493 significantly inhibited peripheral TNF synthesis, and intact vagus nerves were required to prevent increases in serum TNF. The mechanism through which CNI-1493 activates the vagus nerve is unknown, but increased vagus nerve firing has been observed after either intracerebral or intravenous administration of CNI-1493 — an effect that seems to be dependent on specific CNS receptors33.

CNI-1493은 국소 및 전신 염증 동물 모델에서 TNF 합성과 염증 반응을 억제한다⁵⁸. 또한 중증 크론병 소규모 임상시험에서 질환 중증도를 현저히 감소시켰으며, 현재 크론병 대상 대규모 2상 임상시험에서 평가 중이다⁵⁹. 예상치 못하게도 최근 연구 결과에 따르면, 생체 내에서의 CNI-1493의 TNF 억제 활성은 콜린성 항염증 경로에 의존하며, CNI-1493은 미주신경의 약리학적 자극제로 기능하는 것으로 밝혀졌다³²,⁶⁰: 소량의 CNI-1493을 뇌내 투여했을 때 말초 TNF 합성이 현저히 억제되었으며, 혈청 TNF 증가를 방지하기 위해서는 온전한 미주 신경이 필요했습니다. CNI-1493이 미주신경을 활성화하는 기전은 알려지지 않았으나, 뇌내 또는 정맥 내 CNI-1493 투여 후 미주신경 발화 증가가 관찰되었으며, 이 효과는 특정 중추신경계 수용체에 의존하는 것으로 보인다³³.

It is likely that other experimental and clinically approved therapeutic agents suppress peripheral inflammation by activating pathways in the CNS. Small doses of a-MSH applied intracerebrally inhibited pulmonary myeloperoxidase activity in mice exposed to endotoxin61 and suppressed the development of intradermal oedema induced by exposure to TNF or IL-1 (ref. 62). Specific anti-inflammatory responses have been observed in response to intracerebral application of salicylates, but not dexamethasone63. The cardiac antiarrhythmic drug amiodarone has been identified as an inhibitor of TNF synthesis in monocytes in vitro64, but it also functions as a potent stimulator of vagus nerve activity65. Systemic administration of the non-steroidal anti-inflammatory drugs aspirin, indomethacin and ibuprofen substantially increases vagus nerve activity66. Although this vagus nerve response had been studied in the context of increasing gastric acidity and ulcer formation, knowledge of the cholinergic anti-inflammatory pathways raises the possibility that the vagus-nerve-stimulating activity of these agents may also contribute to their anti-inflammatory action. A better understanding of the CNS receptors, pathways and neural mechanisms that activate the vagus nerve to inhibit production of TNF should facilitate development of this pharmacological ‘vagus-nervestimulating’ approach.

다른 실험적 및 임상적으로 승인된 치료제들도 중추신경계의 경로를 활성화하여 말초 염증을 억제할 가능성이 있다. 소량의 α-MSH를 뇌내 투여했을 때 내독소에 노출된 생쥐의 폐 골수과산화효소 활성을 억제했으며(61), TNF 또는 IL-1 노출로 유발된 피부내 부종 발생을 억제했다(62). 살리실산염의 뇌내 투여에 대한 특이적 항염증 반응이 관찰된 반면, 덱사메타손에서는 그러한 반응이 관찰되지 않았다63. 심장 항부정맥제인 아미오다론은 시험관 내에서 단핵구에서 TNF 합성을 억제하는 것으로 확인되었으나64, 동시에 미주신경 활동을 강력히 자극하는 기능도 수행한다65. 비스테로이드성 항염증제인 아스피린, 인도메타신, 이부프로펜의 전신 투여는 미주신경 활동을 현저히 증가시킵니다(66). 비록 이 미주신경 반응은 위산 증가 및 궤양 형성과 관련하여 연구되었지만, 콜린성 항염증 경로에 대한 지식은 이러한 약물의 미주신경 자극 활성이 항염증 작용에도 기여할 가능성을 제기합니다. 중추신경계 수용체, 경로 및 미주신경 활성화를 통해 TNF 생성을 억제하는 신경 기전에 대한 이해가 깊어질수록, 이러한 약리학적 ‘미주신경 자극’ 접근법의 개발이 용이해질 것이다.

Another experimental therapeutic approach is based on direct electrical stimulation of the vagus nerve. So far, more than 10,000 individuals have received implantable vagus nerve stimulators for the treatment of epilepsy67,68. Vagus nerve stimulation in humans with small, pacemaker-like devices is safe, well tolerated and not associated with increased rates of infection. But the immunological effects of this approach have not been reported and, indeed, it will interesting to assess whether stimulating the vagus nerve in humans modulates TNF synthesis and inflammation. In place of implantable devices, it should be possible to develop pharmacological approaches that target the peripheral macrophage receptor to inhibit TNF synthesis. A precedent for this approach has been already achieved in the clinic, because nicotine administration is significantly efficacious in reducing the severity of ulcerative colitis69. Other preclinical studies using standard murine models of diabetes have shown that nicotine reduces the incidence of diabetes by reducing pancreatic concentrations of TNF and other cytokines70. Unanticipated activities of the cholinergic anti-inflammatory pathway in inflammatory disease and in non-immune cells might be determined by further studies. Some of the earliest studies of the nervous system and inflammation examined the effects of pavlovian conditioning on intra-abdominal inflammatory responses71. Behavioural conditioning using models of learned association can reproducibly influence acute inflammatory responses and alter the course of experimental inflammatory diseases in animals and humans72–74. Hypnosis and meditation can significantly increase vagus nerve output and have been observed to inhibit immediate-type and delayed-type hypersensitivity responses75,76. Biofeedback and acupuncture have been used to modulate vagus nerve activity to alter bowel function, gastric acidity and heart rate77,78. Each of these approaches has been used to reduce experimental inflammation, but the relationships between vagus nerve activity and anti-inflammatory action had not been defined previously. Autonomic dysfunction occurs as a classical complication of rheumatoid arthritis, diabetes and other autoimmune disorders79–81. It is now intriguing to consider whether vagus nerve dysfunction underlies the progression of inflammation, owing to impairment of the cholinergic anti-inflammatory pathway. It is reasonable to propose that, one day, the rational modulation of vagus nerve activity using these or other approaches may provide a therapeutic advantage for inflammatory disease.

또 다른 실험적 치료 접근법은 미주신경에 대한 직접적인 전기적 자극에 기반한다. 지금까지 10,000명 이상의 환자가 간질 치료를 위해 이식형 미주신경 자극기를 이식받았습니다.67,68 소형 박동기 유사 장치를 이용한 인간의 미주신경 자극은 안전하고 내약성이 우수하며 감염률 증가와 연관되지 않습니다. 그러나 이 접근법의 면역학적 효과는 보고된 바 없으며, 실제로 인간의 미주신경 자극이 TNF 합성과 염증을 조절하는지 평가하는 것은 흥미로울 것입니다. 이식형 장치 대신, 말초 대식세포 수용체를 표적으로 삼아 TNF 합성을 억제하는 약리학적 접근법을 개발할 수 있을 것이다. 이 접근법의 선례는 이미 임상에서 확인되었는데, 니코틴 투여가 궤양성 대장염의 중증도를 현저히 감소시키는 데 효과적이기 때문이다69. 당뇨병 표준 생쥐 모델을 사용한 다른 전임상 연구들에서도 니코틴이 췌장의 TNF 및 기타 사이토카인 농도를 감소시켜 당뇨병 발병률을 낮춘다는 것이 밝혀졌다70. 염증성 질환 및 비면역 세포에서 콜린성 항염증 경로의 예상치 못한 작용은 추가 연구를 통해 규명될 수 있다. 신경계와 염증에 관한 초기 연구 중 일부는 복강 내 염증 반응에 대한 파블로프 조건화의 효과를 조사했다71. 학습된 연관성 모델을 이용한 행동 조건화는 동물과 인간에서 급성 염증 반응에 재현 가능한 영향을 미치고 실험적 염증성 질환의 경과를 변화시킬 수 있다72–74. 최면과 명상은 미주신경 출력을 현저히 증가시킬 수 있으며, 즉발형 및 지연형 과민 반응을 억제하는 것으로 관찰되었다75,76. 생체 피드백과 침술은 미주신경 활동을 조절하여 장 기능, 위산도 및 심박수를 변화시키는 데 활용되었다77,78. 이러한 접근법들은 각각 실험적 염증을 감소시키는 데 사용되었으나, 미주신경 활동과 항염증 작용 간의 관계는 이전에 정의된 바 없었다. 자율신경 기능 장애는 류마티스 관절염, 당뇨병 및 기타 자가면역 질환의 전형적인 합병증으로 발생한다⁷⁹⁻⁸¹. 이제 콜린성 항염증 경로의 손상으로 인해 미주 신경 기능 장애가 염증 진행의 기반이 되는지 고려하는 것이 흥미롭다. 이러한 방법이나 다른 접근법을 통해 미주 신경 활동을 합리적으로 조절하는 것이 언젠가 염증성 질환에 대한 치료적 이점을 제공할 수 있을 것이라고 제안하는 것은 타당하다.