総説 炎症性筋疾患 ICU-aquired weaknessへの補助的病態解析として

Inflammatory Muscle Diseases.
Dalakas MC.
N Engl J Med. 2015 Apr 30;372(18):1734-1747.

 

＜松田直之 コメント＞
　全身性炎症では筋力低下が生じますが，救急・集中治療医は，その分子機構をより深く理解して，創薬を講じる必要があります。読み応えのある応用性のある総説です。当教室のみなの必須・必読論文です。しかし，このシェーマは熟成されておらず，この分子関連のたくさんの脱落がを改良することが重要です。

Inflammatory myopathies are the largest group of potentially treatable myopathies in children and adults. They constitute a heterogeneous group of disorders that are best classified, on the basis of distinct clinicopatho- logic features, in four subtypes: dermatomyositis, polymyositis, necrotizing auto- immune myositis, and inclusion-body myositis (throughout this review, I use this term to refer specifically to sporadic inclusion-body myositis).1-6 A fifth subtype, termed overlap myositis, is also beginning to be recognized. The identification of the correct subtype and the distinction of these conditions from other diseases that have characteristics that mimic these conditions is fundamental, because each subtype has a different prognosis and response to therapies. This review reflects the current knowledge of these conditions, highlights how best to avoid erroneous diagnoses, describes the main clinicopathologic and immunologic features, and pro- vides practical guidelines regarding therapies.



　Patients with inflammatory myopathies have increasing difficulty with tasks re- quiring the use of proximal muscles, such as getting up from a chair, climbing steps, or lifting objects.Tasks requiring distal muscles, such as buttoning or holding objects, are affected early in inclusion-body myositis but only in advanced cases of polymyositis, dermatomyositis, and necrotizing autoimmune myositis. The ocular muscles are spared in all subtypes, but facial muscles are commonly affected in inclusion-body myositis.3 In all disease subtypes, neck-extensor and pharyngeal muscles can be involved, which results in difficulty holding up the head (head drop) or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be affected. Muscle atrophy is detected early in inclusion-body myositis, with selective atrophy of the quadriceps and forearm muscles, but it develops in all subtypes if the weakness is severe and chronic. Myalgia and muscle tenderness may occur, especially in patients with the antisynthetase syndrome (see the Glossary), but if pain is severe and the weakness follows a “breakaway” pattern, in which the pa- tient has difficulty sustaining effort, fasciitis or fibromyalgia should be ruled out.
　
　Extramuscular manifestations may occur in all inflammatory myopathies, although they occur in inclusion-body myositis only in rare cases; these manifesta- tions include systemic symptoms, such as fever, arthralgia, and Raynaud’s phe- nomenon, as seen in the antisynthetase syndrome; cardiac arrhythmias or ventricular dysfunction, in relatively uncommon cases in which the affected car- diac muscle is clinically symptomatic; and pulmonary complications, due primar- ily to interstitial lung disease, which are reported in 10 to 40% of patients. The prevalence of interstitial lung disease, a condition that is best detected with high- resolution computed tomography, is as high as 70% among patients with anti–his- tidyl–transfer RNA (tRNA) synthetase (anti-Jo-1) or anti–melanoma differentiation–associated protein (MDA)–5 antibodies.

論文紹介 好中球機能

急性期免疫管理ブランチ2015

本年は，集中治療管理に免疫管理の重要性を盛り込んだものですから，

国内のいろいろな講演でも，一部を紹介していきます。

以下の論文は，本年の私のMEIDAI免疫管理バンドルの「好中球ブランチ」の中で紹介する文献です。

Crit Care. 2015 Feb 25;19(1):57. doi: 10.1186/s13054-015-0778-z.

The diagnostic and prognostic significance of monitoring blood levels of immature neutrophils in patients with systemic inflammation.

Mare TA1,2, Treacher DF3,4, Shankar-Hari M5,6, Beale R7,8, Lewis SM9,10,11, Chambers DJ12, Brown KA13,14,15.

Author information

 

Abstract

INTRODUCTION: 

In this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.

METHODS: 

Blood samples were routinely taken from 136 critically ill patients within 48 hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other's results, and patients were retrospectively characterised into those with SIRS (n = 122) and those without SIRS (n = 14). The patients with SIRS were further subdivided into categories of definite sepsis (n = 51), possible sepsis (n = 32) and N-I SIRS (n = 39). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.

RESULTS: 

With the first criterion, band cells were present in most patients with SIRS (mean = 66%) when compared with no SIRS (mean = 29%; P

CONCLUSIONS: 

Raised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.

 

Crit Care Med. 2013 Mar;41(3):820-32. doi: 10.1097/CCM.0b013e318274647d.

Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome.

Drifte G1, Dunn-Siegrist I, Tissières P, Pugin J.

Author information

 

Abstract

OBJECTIVE: 

A hallmark of sepsis and severe systemic inflammatory response syndrome (SIRS) is the massive recruitment of immature neutrophils from the bone marrow into the circulation (left shift, band forms). Their capacity to participate in innate defense against bacteria is ill defined. We aimed at comparing various innate immune functions of mature vs. immature neutrophils circulating during sepsis and SIRS.

DESIGN: 

Prospective, observational cohort study.

SETTING:Tertiary level ICU and associated research laboratory.

PATIENTS: 

Thirty-three ICU patients with sepsis; 12 ICUs with SIRS; 32 healthy volunteers.

INTERVENTIONS: 

Twenty milliliters of whole heparinized blood was used for in vitro studies including neutrophil viability and apoptosis, surface expression of CD16, Toll-like receptors () 4 and TLR2, CD14, MD-2, HLA-DP,-DQ and -DR, and CXCR2, chemotaxis, phagocytosis, bacterial killing, and tumor necrosis factor-α/interleukin-10 baseline intracellular cytokine levels.

MEASUREMENTS AND MAIN RESULTS: 

Immature neutrophils were capable of mediating important innate immune functions such as bacterial phagocytosis and killing via the production of reactive oxygen species, although less efficiently than mature neutrophils. Immature neutrophils had a longer life span and resistance to spontaneous apoptosis, and could mature ex vivo. They expressed lower levels of receptors for bacterial molecules such as CD14 and MD-2 and migrated less efficiently than mature granulocytes. Immature neutrophils had higher basal intracellular tumor necrosis factor-α/interleukin-10 ratio than that of mature neutrophils, suggesting a proinflammatory phenotype. No significant differences were observed between immature neutrophils isolated from patients with sepsis and those from patients with severe SIRS.

CONCLUSIONS: 

Despite their "immaturity", band forms are capable of mediating crucial innate immune functions during severe infections and sepsis. Their fate and capacity to mature in vivo remain to be determined.

総説 線維化と多臓器不全

Fibrosis--a common pathway to organ injury and failure.
Rockey DC, Bell PD, Hill JA.
N Engl J Med. 2015;372:1138-49.

＜松田直之 コメント＞
現在，当講座が全身管理として注目している病態は，炎症後の臓器内線維症です。
この診療および研究が重要と評価し，特に線維芽細胞のリセッティングをターゲットとした研究も推進中です。
救急・集中治療領域における新規病態学・創薬のターゲットと考えています。
炎症を軽減する方策を戦略化一方で，炎症後の線維化増強を正常化させるのです。
当講座は，2015年春季抄読会で，この総説を取り上げる予定です。

Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminates in tissue fibrosis. Although this fibrogenic response may have adaptive features in the short term, when it progresses over a prolonged period of time, parenchymal scarring and ultimately cellular dysfunction and organ failure ensue.

We and others have proposed four major phases of the fibrogenic response. First is initiation of the response, driven by primary injury to the organ. The second phase is the activation of effector cells, and the third phase is the elaboration of extracellular matrix, both of which overlap with the fourth phase, during which the dynamic deposition (and insufficient resorption) of extracellular matrix promotes progression to fibrosis and ultimately to end-organ failure.

The fact that diverse diseases in different organ systems are associated with fibrotic changes suggests common pathogenic pathways. This “wounding response” is orchestrated by complex activities within different cells in which specific molecular pathways have emerged. Cellular constituents include inflammatory cells (e.g., macrophages and T cells), epithelial cells, fibrogenic effector cells, endothelial cells, and others. Many different effector cells, including fibroblasts, myofibroblasts, cells derived from bone marrow, fibrocytes, and possibly cells derived from epithelial tissues (epithelial-to-mesenchymal transition) have been identified; there is some controversy regarding the identity of specific effectors in different organs. Beyond the multiple cells essential in the wounding response, core molecular pathways are critical; for example, the transforming growth factor beta (TGF-β) pathway is important in virtually all types of fibrosis.

As fibrosis progresses, myofibroblasts proliferate and sense physical and biochemical stimuli in the local environment by means of integrins and cell-surface molecules; contractile mediators trigger pathological tissue contraction. This chain of events, in turn, causes physical organ deformation, which impairs organ function. Thus, the biology of fibrogenesis is dynamic, although the degree of plasticity appears to vary from organ to organ.

Although we understand many of the cellular and molecular processes underlying fibrosis, there are few effective therapies and fewer that target fibrogenesis specifically. These facts highlight the need for a deeper comprehension of the pathogenesis of fibrogenesis and the translation of this knowledge to novel treatments.

総説 糖尿病性ケトアシドーシス

Acid-base problems in diabetic ketoacidosis.
Kamel KS, Halperin ML.
N Engl J Med. 2015;372:546-54.

＜松田直之 コメント＞
我々の救急・集中治療部にも，年間で4例程度の重症な糖尿病性ケトアシドーシスの搬入があります。
とても良く記載されている素晴らしい総説です。

This review focuses on three issues facing clinicians who care for patients with diabetic ketoacidosis; all of the issues are related to acid–base disorders. The first issue is the use of the plasma anion gap and the calculation of the ratio of the change in this gap to the change in the concentration of plasma bicarbonate in these patients; the second concerns the administration of sodium bicarbonate; and the third is the possible contribution of intracellular acidosis to the development of cerebral edema, particularly in children with diabetic ketoacidosis. In this article, we examine the available data and attempt to integrate the data with principles of physiology and metabolic regulation and provide clinical guidance.










強い要望により，学術面のみの再開とします。
2015年3月27日　松田直之

文献 Autophagy 2012 January; 8(1): 47–62

Autophagy. 2012 January; 8(1): 47–62.
Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence life span

Mai S, Muster B, Bereiter-Hahn J, Jendrach M.
Kinematic Cell Research Group; Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Frankfurt/Main, Germany.


Mitochondrial health is maintained by the quality control mechanisms of mitochondrial dynamics (fission and fusion) and mitophagy. Decline of these processes is thought to contribute to aging and neurodegenerative diseases. To investigate the role of mitochondrial quality control in aging on the cellular level, human umbilical vein endothelial cells (HUVEC) were subjected to mitochondria-targeted damage by combining staining of mitochondria and irradiation. This treatment induced a short boost of reactive oxygen species, which resulted in transient fragmentation of mitochondria followed by mitophagy, while mitochondrial dynamics were impaired. Furthermore, targeted mitochondrial damage upregulated autophagy factors LC3B, ATG5 and ATG12. Consequently these proteins were overexpressed in HUVEC as an in vitro aging model, which significantly enhanced the replicative life span up to 150% and the number of population doublings up to 200%, whereas overexpression of LAMP-1 did not alter the life span. Overexpression of LC3B, ATG5 and ATG12 resulted in an improved mitochondrial membrane potential, enhanced ATP production and generated anti-apoptotic effects, while ROS levels remained unchanged and the amount of oxidized proteins increased. Taken together, these data relate LC3B, ATG5 and ATG12 to mitochondrial quality control after oxidative damage, and to cellular longevity.

文献紹介 全身性炎症におけるメラトニンを再考する

1. Sircadian mechanisms in the regulation of melatonin synthesis: disruption with light at night and the pathophysiological consequences
Russel J. Reiter, Dun Xian Tan, Emilio Sanchez-Barcelo, Maria D. Mediavilla, Eloisa Gitto, Ahmet Korkmaz. J Exp Integr Med. 2011; 1(1): 13-22

In the past two decades, the results of a number of epidemiological studies have uncovered an association between excessive light exposure at night and the prevalence of cancer. Whereas the evidence supporting this link is strongest between nighttime light and female breast and male prostate cancer, the frequency of other tumor types may also be elevated. Individuals who have the highest reported increase in cancer are chronic night shift workers and flight attendants who routinely fly across numerous time zones.
There are at least two obvious physiological consequences of nighttime light exposure, i.e., a reduction in circulating melatonin levels and disruption of the circadian system (chronodisruption). Both these perturbations in experimental animals aggravate tumor growth. Melatonin has a long investigative history in terms of its ability to stymie the growth of many tumor types. Likewise, in the last decade chronodisruption has been unequivocally linked to a variety of abnormal metabolic conditions including excessive tumor growth.
This brief review summarizes the processes by which light after darkness onset impedes melatonin production and disturbs circadian rhythms. The survey also reviews the evidence associating the ostensible danger of excessive nighttime light pollution to cancer risk. If an elevated tumor frequency is definitively proven to be a consequence of light at night and/or chronodisruption, it seems likely that cancer will not be the exclusive pathophysiological change associated with the rampant light pollution characteristic of modern societies.

2. Beneficial effects of endogenous and exogenous melatonin on neural reconstruction and functional recovery in an animal model of spinal cord injury 2012; 52(1): 107.

The purpose of this study was to investigate the beneficial effects of endogenous and exogenous melatonin on functional recovery in an animal model of spinal cord injury (SCI). Eight-week-old male Sprague-Dawley (SD, 250–260 g) rats were used for contusion SCI surgery. All experimental groups were maintained under one of the following conditions: 12/12-hr light/dark (L/D) or 24:0-hr constant light (LL). Melatonin (10 mg/kg) was injected subcutaneously for 4 wk, twice daily (07:00, 19:00). Locomotor recovery, inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein gene expression, and muscle atrophy-related genes, including muscle atrophy F-box (MAFbx) and muscle-specific ring-finger protein 1 (MuRF1) gene expression were evaluated. Furthermore, autophagic signaling such as Beclin-1 and LC3 protein expression was examined in the spinal cord and in skeletal muscle. The melatonin treatment resulted in increased hind-limb motor function and decreased iNOS mRNA expression in the L/D condition compared with the LL condition (P < 0.05), indicating that endogenous melatonin had neuroprotective effects. Furthermore, the MAFbx, MuRF1 mRNA level, and converted LC3 II protein expression were decreased in the melatonin-treated SCI groups under the LL (P < 0.05), possibly in response to the exogenous melatonin treatment. Therefore, it seems that both endogenous and exogenous melatonin contribute to neural recovery and to the prevention of skeletal muscle atrophy, promoting functional recovery after SCI. Finally, this study supports the benefit of endogenous melatonin and use of exogenous melatonin as a therapeutic intervention for SCI.

3. Glucose: A vital toxin and potential utility of melatonin in protecting against the diabetic state
Molecular and Cellular Endocrinology 2012; 349(2): 128.

The molecular mechanisms including elevated oxidative and nitrosative reactants, activation of pro-inflammatory transcription factors and subsequent inflammation appear as a unified pathway leading to metabolic deterioration resulting from hyperglycemia, dyslipidemia, and insulin resistance. Consistent evidence reveals that chronically-elevated blood glucose initiates a harmful series of processes in which toxic reactive species play crucial roles. As a consequence, the resulting nitro-oxidative stress harms virtually all biomolecules including lipids, proteins and DNA leading to severely compromised metabolic activity. Melatonin is a multifunctional indoleamine which counteracts several pathophysiologic steps and displays significant beneficial effects against hyperglycemia-induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants and blocking transcriptional factors which induce pro-inflammatory cytokines. These functions contribute to melatonin’s antioxidative, anti-inflammatory and possibly epigenetic regulatory properties. Additionally, melatonin restores adipocyte glucose transporter-4 loss and eases the effects of insulin resistance associated with the type 2 diabetic state and may also assist in the regulation of body weight in these patients. Current knowledge suggests the clinical use of this non-toxic indoleamine in conjunction with other treatments for inhibition of the negative consequences of hyperglycemia for reducing insulin resistance and for regulating the diabetic state.

4. Plasma Melatonin and Urinary 6-Hydroxymelatonin Levels in Patients with Pulmonary Tuberculosis
Inflammation 2012

Tuberculosis (TB) is the second most frequent cause of death in the world, after AIDS. Delay in diagnosing TB is an important worldwide problem. It seriously threatens public health. Cell-mediated immune responses play an important role in the pathogenesis of TB infection. The course of Mycobacterium tuberculosis (MTb) infection is regulated by two distinct T cell cytokine patterns. Melatonin is a biomolecule (mainly secreted by the pineal gland) with free radical scavenging, antioxidant and immunoregulatory properties. Melatonin has both its direct and indirect immunomodulatory effects on the immune system. In this study, we measured plasma melatonin and urine 6-hydroxy melatonin sulphate (6-HMS) concentrations in patients with newly diagnosed TB for the purpose of investigating whether there was a relationship between their levels and MTb infection. Thirty-one newly diagnosed patients presenting with active TB and 31 healthy subjects as the control group were included in this study. Blood and 24-h urine samples were collected from all individuals. Plasma melatonin levels and urine 6-HMS were measured. Our results show that in patients with TB, mean melatonin and 6-HMS concentrations were significantly lower than in the control subjects (p&#8201;=&#8201;0.037, p&#8201;<&#8201;0.001, respectively). We believe that the treatment of TB patients with melatonin might result in a wide range of health benefits including improved quality of life and reduced severity of infection in these patients. Supplementation with melatonin may be considered as an adjunctive therapy to classic treatment of pulmonary TB, especially during the acute phase of infection.

5. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”?
Rev. Med. Virol. 2012

Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein. Copyright &#169; 2012 John Wiley & Sons, Ltd.

6. Gene regulation by melatonin linked to epigenetic phenomena
Gene 2012:503;1-11

Many exogenous (e.g., toxins, chemicals, ultraviolet, cigarette smoke) and endogenous (e.g., hyperglycemia, dyslipidemia, cytokines, chemokines) agents disrupt the intracellular environment and result in a massive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The molecular damage that ROS/RNS induce is referred to as nitrooxidative stress. The cellular consequences of nitrooxidative stress include lipid peroxidation, protein oxidation and DNA damage. Additionally, ROS and RNS deplete cellular defenses and initiate inflammation. It is widely accepted that nitrooxidative stress and inflammation play important roles in the pathogenesis of a variety of human diseases and sequelae. Several processes are crucial to overcome the damaging cellular events caused by nitrooxidative stress, e.g., scavenging both ROS and RNS, induction of defense mechanisms and alleviating/suppressing inflammation are essential. Both endogenous and pharmacological concentrations of melatonin have long been known to play role in the direct scavenging of ROS and RNS as well as inducing antioxidant defense mechanisms and ameliorating inflammation. The current review summarizes research related to two major transcription factors that participate in these processes and summarizes how melatonin regulates antioxidant and pro-inflammatory genes via epigenetic on/off mechanisms.

<font color="red">7. Melatonin in bacterial and viral infections with focus on sepsis: a review.
Srinivasan V, Mohamed M, Kato H.
Recent Pat Endocr Metab Immune Drug Discov. 2012 Jan;6(1):30-9. Review.

この総説は読まれてみて下さい。敗血症におけるメラトニン研究は，現在このレベルで留まっています。

Melatonin is a versatile molecule, synthesized not only by the pineal gland, but also in small amounts by many other organs like retina, gastrointestinal tract, thymus, bone marrow, lymphocytes etc. It plays an important role in various functions of the body like sleep and circadian rhythm regulation, immunoregulatory mechanism, free radical scavenger, antioxidant functions, oncostatic actions, control of reproductive functions, regulation of mood etc. Melatonin has also been found to be effective in combating various bacterial and viral infections. Its administration has been shown to be effective in controlling chlamydial infections, infections induced by Mycobacterium tuberculosis, and also in many viral infections. Molecular mechanisms of anti microbial actions of melatonin have suggested to be due to effects on free radical formation, direct regulation of duplication of bacteria, depletion of intracellular substrates like iron etc. Besides, it is effective in sepsis as demonstrated in various animal models of septic shock. Melatonin's protective action against sepsis is suggested to be due to its antioxidant, immunomodulating and inhibitory actions against the production and activation of pro-inflammatory mediators. Use of melatonin has been beneficial in treating premature infants suffering from severe respiratory distress syndrome and septic shock. It has a potential therapeutic value in treating septic shock and associated multi organ failure in critically ill patients in addition to its antimicrobial and antiviral actions. The patents related to melatonin's use for treatment of bacterial infections and its use in clinical disorders are included.

8. Melatonin in septic shock: some recent concepts.
Srinivasan V, Pandi-Perumal SR, Spence DW, Kato H, Cardinali DP.
J Crit Care. 2010 Dec;25(4):656.e1-6.

Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation, immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and regulation of mood. Melatonin has also been reported as effective in combating various bacterial and viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial function and in preventing apoptosis. In a number of animal models of septic shock, as well as in patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the treatment of multiorgan failure are discussed.

2012 SCCM Consensus： Hydroxyethyl Starch Harmful in Severe Sepsis（HES要注意）

2012 SCCM Consensus in HES usage in Severe Sepsis

Based on the results of several small trials, the safety of colloid solutions containing high-molecular-weight hydroxyethyl starch (HES) has been questioned in patients with severe sepsis. In the July 12 issue of The New England Journal of Medicine, Perner and investigators from the 6S Trial Group and the Scandinavian Critical Care Trials Group reported the results from a multicenter, blinded, stratified, parallel-group randomized trial conducted in 26 Scandinavian intensive care units from 2009 to 2011. The effects of HES (130/0.42) were compared to those of Ringer’s acetate on the composite outcomes of death or end-stage renal failure in patients with severe sepsis.

Computerized allocation was used to blindly randomize 804 patients. Treatment assignments were concealed from investigators, clinicians and patients. Adults older than 18 and fulfilling criteria for severe sepsis were enrolled. The primary outcome was death or dependence on dialysis 90 days after randomization. The study was appropriately powered to detect an absolute difference in the primary outcome, with multivariate analyses used to adjust for differences in baseline variables.

The study followed 398 patients in the HES group and 400 in the Ringer’s group (N=798 total) for at least 90 days. Baseline characteristics were similar in the two groups, with each having an incidence of acute kidney injury over 35%. The median cumulative volume of fluid received was not statistically significantly different between the two groups. More patients in the HES group received blood products and required renal replacement therapy. The primary outcome of death was higher in the HES group (relative risk [RR], 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 53% of patients in the HES group died compared to 43% in the Ringer’s group. The authors hypothesized that one explanation for the findings may be that HES is deposited in tissues, and may act as a toxic foreign body.

This well-conducted study conformed to a modified intention-to-treat protocol. Although a high number of patients with acute kidney injury were included, this comorbidity was evenly balanced with the randomized design. Patients received strikingly similar amounts of fluids, though the trial did not employ advanced hemodynamic monitoring or protocols for titrating fluids.

HES was associated with an increase in absolute risk of death (number needed to harm=13). Based on the results of this trial and previous work in this area, the use of HES should be critically examined as an option for colloid resuscitation in patients with severe sepsis. Patients with severe sepsis who received HES were at increased risk of death at 90 days, more likely to receive renal-replacement therapy, and were alive for fewer days once discharged from the hospital.

※ 敗血症は全身性炎症の代表的病態です。このような検証が行われるまでもなく，重症敗血症や敗血症性ショックにHESを使うことはないと思いますがが，これは敗血症にのみ有害なわけではありません。理論的には炎症性手術においてHESを用いれば臓器不全が進行する可能性があり，既に一臓器以上の臓器不全を持っている場合には，90日死亡率にも影響が出る可能性があるということです。特に，術後に腎機能を低下させる可能性については，炎症性サイトカインの増加する手術において，極めてリスクが高いと評価されます。

Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis
N Engl J Med 2012; 367:124-134
Anders Perner, M.D., Ph.D., Nicolai Haase, M.D., Anne B. Guttormsen, M.D., Ph.D., Jyrki Tenhunen, M.D., Ph.D., Gudmundur Klemenzson, M.D., Anders Åneman, M.D., Ph.D., Kristian R. Madsen, M.D., Morten H. Møller, M.D., Ph.D., Jeanie M. Elkjær, M.D., Lone M. Poulsen, M.D., Asger Bendtsen, M.D., M.P.H., Robert Winding, M.D., Morten Steensen, M.D., Pawel Berezowicz, M.D., Ph.D., Peter Søe-Jensen, M.D., Morten Bestle, M.D., Ph.D., Kristian Strand, M.D., Ph.D., Jørgen Wiis, M.D., Jonathan O. White, M.D., Klaus J. Thornberg, M.D., Lars Quist, M.D., Jonas Nielsen, M.D., Ph.D., Lasse H. Andersen, M.D., Lars B. Holst, M.D., Katrin Thormar, M.D., Anne-Lene Kjældgaard, M.D., Maria L. Fabritius, M.D., Frederik Mondrup, M.D., Frank C. Pott, M.D., D.M.Sci., Thea P. Møller, M.D., Per Winkel, M.D., D.M.Sci., and Jørn Wetterslev, M.D., Ph.D. for the 6S Trial Group and the Scandinavian Critical Care Trials Group



BACKGROUND
Hydroxyethyl starch (HES) is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
METHODS
In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
RESULTS
Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
CONCLUSIONS
Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.)


Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007594.

Dart AB, Mutter TC, Ruth CA, Taback SP.
Source
Department of Pediatrics and Child Health, University of Manitoba, FE-009 840 Sherbrook St, Winnipeg, Manitoba, Canada, R3A 1S1.
Abstract
BACKGROUND:
Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function.
OBJECTIVES:
To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations.
SEARCH STRATEGY:
We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles.
SELECTION CRITERIA:
Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance.
DATA COLLECTION AND ANALYSIS:
Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model.
MAIN RESULTS:
The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded.
AUTHORS' CONCLUSIONS:
Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.


循環血液量増加に関してはアルブミンもHESも有効 by びんちゃん

Su F, Wang Z, Cai Y, Rogiers P, Vincent JL.
Shock. 2007 May;27(5):520-6.
Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer's lactate-does it really make a difference?

Abstract
The aim of this study was to investigate whether the type of i.v. fluid administered has an impact on outcome in an animal model of septic shock. The study included 28 anesthetized, invasively monitored, mechanically ventilated female sheep (29.5 +/- 4.0 kg), which received 0.5 g/kg body weight of feces into the abdominal cavity to induce peritonitis. During the surgical operation and 4 h after feces spillage, only Ringer's lactate (RL) was administered in all animals. Thereafter, animals were randomized to receive continuous infusions of RL (n = 7) alone or combined with either 20% albumin (n = 7, volume ratio to RL 1:10) or 6% hydroxyethyl starch (HES) (n = 7, volume ratio to RL 1:1), or gelatin alone (n= 7, no volume limitation). Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. No antibiotics or vasoactive drugs were administered, and animals were monitored until their spontaneous death. Hemodynamic variables were better with HES and albumin than with the other fluids, as reflected by higher stroke volume, cardiac index, and oxygen delivery (all P < 0.05). Hydroxyethyl-starch-treated animals also had lower arterial lactate concentrations (P < 0.01). However, times to develop hypotension and oliguria were similar in all groups. Blood interleukin (IL) 6 concentrations were significantly increased in all groups. The mean survival time was similar in all groups. In this clinically relevant model of prolonged septic shock, albumin and HES solution resulted in higher cardiac output, oxygen delivery, and lower blood lactate levels than gelatin and RL; however, the choice of i.v. fluid did not affect outcome.

文献紹介 Gut-origin sepsis 腸管傍リンパ節装置と炎症について

敗血症は大量のサイトカイン産生病態であり，蛋白と脂質の異化を基盤とします。
このために炎症の急性極期を含めて栄養管理が極めて大切なのですが，
多くの施設では，急性期栄養管理が不十分で痩せや意識障害が進行してしまったり，
さらに腸管炎症の軽減についての十分な対応，すなわち早期経腸栄養が行われていないようです。
本日の朝の討論は，バクテリアルトランスロケーションと腸管由来敗血症の違い，
そして腸管傍リンパ節装置における炎症進展の機序でしたが，
この内容は今後，より厳密に評価されるものであり，
まだまだ，この病態生理の詳細は発展途上にあると考えています。


Surgeon. 2012 Apr 23. [Epub ahead of print]
Gut-origin sepsis: Evolution of a concept.
Deitch EA.
Department of Surgery, University of Medicine and Dentistry New Jersey, Newark, New Jersey, USA.

Abstract
The concept of bacterial translocation and gut-origin sepsis as a cause of systemic infectious complications and the multiple organ dysfunction syndrome (MODS) in surgical and ICU patients has emerged over the last several decades, although the exact clinical relevance of these phenomenon continue to be debated. Thus, the goal of this review will be to trace the evolution of gut-origin sepsis and gut-induced MODS and put these disorders and observations into clinical perspective. Additionally, the mechanisms leading to gut-derived complications will be explored as well as therapeutic options to limit or prevent these complications. From this work, several major conclusions emerge. First, that bacterial translocation occurs clinically and is responsible for increased infectious complications in patients undergoing major abdominal surgery. However, the phenomenon of bacterial translocation is not sufficient to explain the development of MODS in ICU patients. Instead, the development of MODS in these high-risk patients is likely due to gut injury and the systemic spread of non-microbial, tissue-injurious factors that reach the systemic circulation via the intestinal lymphatics. These observations have resulted in the gut-lymph hypothesis of MODS.

Ann N Y Acad Sci. 2010 Oct;1207 Suppl 1:E103-11.
Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction.
Deitch EA.

Abstract
Major trauma, shock, sepsis, and other conditions can lead to the acute respiratory distress syndrome (ARDS), which may progress to the highly lethal multiple organ dysfunction syndrome (MODS). Although a number of therapeutic strategies have been initiated, their success has been limited largely due to an incomplete understanding of the biology of MODS. However, recent studies indicate that the intestinal lymphatics serve as the primary route for nonbacterial, tissue injurious gut-derived factors, which can induce acute ARDS and MODS. The gut lymph hypothesis of ARDS and MODS thus helps clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph and not the liver (i.e., mesenteric lymph enters the subclavian vein via the thoracic duct, which, in turn, empties directly into the heart and lungs), it would explain the clinical observation that the lung is generally the first organ to fail. Second, this hypothesis provides new pathophysiologic information, thereby providing a basis for novel therapies. Finally, by studying the composition of lymph, MODS-inducing factors can be isolated and identified.

JC文献 Syndecan-4の血管系における役割

2012年4月12日　救急・ICU　Journal Clubの1つの討議内容　杤久保順平先生担当

Xiahui Tan, Najwa Khalil, Candice Tesarik, Karunasri Vanapalli, Viki Yaputra, Hatem Alkhouri, Brian G. G. Oliver, Carol L. Armour, and J. Margaret Hughes
Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases
Am J Physiol Lung Cell Mol Physiol April 1, 2012 302:L700-L710; published ahead of print January 20, 2012


In asthma, airway smooth muscle (ASM) chemokine secretion can induce mast cell recruitment into the airways. The functions of the mast cell chemoattractant CXCL10, and other chemokines, are regulated by binding to heparan sulphates such as syndecan-4. This study is the first demonstration that airway smooth muscle cells (ASMC) from people with and without asthma express and shed syndecan-4 under basal conditions. Syndecan-4 shedding was enhanced by stimulation for 24 h with the Th1 cytokines interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α), but not interferon-γ (IFNγ), nor the Th2 cytokines IL-4 and IL-13. ASMC stimulation with IL-1β, TNF-α, and IFNγ (cytomix) induced the highest level of syndecan-4 shedding. Nonasthmatic and asthmatic ASM cell-associated syndecan-4 protein expression was also increased by TNF-α or cytomix at 4–8 h, with the highest levels detected in cytomix-stimulated asthmatic cells. Cell-associated syndecan-4 levels were decreased by 24 h, whereas shedding remained elevated at 24 h, consistent with newly synthesized syndecan-4 being shed. Inhibition of ASMC matrix metalloproteinase-2 did not prevent syndecan-4 shedding, whereas inhibition of ERK MAPK activation reduced shedding from cytomix-stimulated ASMC. Although ERK inhibition had no effect on syndecan-4 mRNA levels stimulated by cytomix, it did cause an increase in cell-associated syndecan-4 levels, consistent with the shedding being inhibited. In conclusion, ASMC produce and shed syndecan-4 and although this is increased by the Th1 cytokines, the MAPK ERK only regulates shedding. ASMC syndecan-4 production during Th1 inflammatory conditions may regulate chemokine activity and mast cell recruitment to the ASM in asthma.


さらにこれを評価しておくこと

Role of vessel wall and bone marrow syndecan-4 in neointimal hyperplasia: the plot thickens.
Caplice NM.
Arterioscler Thromb Vasc Biol. 2011 May;31(5):952-3.

CXCR7 and syndecan-4 are potential receptors for CXCL12 in human cytotrophoblasts.
Schanz A, Baston-Bust D, Krussel JS, Heiss C, Janni W, Hess AP.
J Reprod Immunol. 2011 Apr;89(1):18-25.

Synectin/syndecan-4 regulate coronary arteriolar growth during development.
Dedkov EI, Thomas MT, Sonka M, Yang F, Chittenden TW, Rhodes JM, Simons M, Ritman EL, Tomanek RJ.
Dev Dyn. 2007 Jul;236(7):2004-10.

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways.
Julien MA, Wang P, Haller CA, Wen J, Chaikof EL.
Am J Physiol Cell Physiol. 2007 Jan;292(1):C517-25.

Effects of L-arginine on fibroblast growth factor 2-induced angiogenesis in a model of endothelial dysfunction.
Voisine P, Li J, Bianchi C, Khan TA, Ruel M, Xu SH, Feng J, Rosinberg A, Malik T, Nakai Y, Sellke FW.
Circulation. 2005 Aug 30;112(9 Suppl):I202-7.

Beta1 and beta3 integrins cooperate to induce syndecan-4-containing cross-linked actin networks in human trabecular meshwork cells.
Filla MS, Woods A, Kaufman PL, Peters DM.
Invest Ophthalmol Vis Sci. 2006 May;47(5):1956-67.

JC文献 肺細動脈細胞におけるオートファジーとアポトーシスのROSを介した相互関係

2012年4月12日　救急・ICU　Journal Clubの1つの討議内容　杤久保順平先生担当

Ru-Jeng Teng, Jianhai Du, Scott Welak, Tongju Guan, Annie Eis, Yang Shi, and Girija G. Konduri
Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension
Am J Physiol Lung Cell Mol Physiol April 1, 2012 302:L651-L663

Autophagy is a process for cells to degrade proteins or entire organelles to maintain a balance in the synthesis, degradation, and subsequent recycling of cellular products. Increased reactive oxygen species formation is known to induce autophagy. We previously reported that increased NADPH oxidase (NOX) activity in pulmonary artery endothelial cells (PAEC) from fetal lambs with persistent pulmonary hypertension (PPHN) contributes to impaired angiogenesis in PPHN-PAEC compared with normal PAEC. We hypothesized that increased NOX activity in PPHN-PAEC is associated with increased autophagy, which, in turn, contributes to impaired angiogenesis in PPHN-PAEC. In the present study, we detected increased autophagy in PPHN-PAEC as shown by increased ratio of the microtubule-associated protein 1 light chain (LC3)-II to LC3-I and increased percentage of green fluorescent protein-LC3 punctate positive cells. Inhibiting autophagy by 3-methyladenine, chloroquine, and beclin-1 knockdown in PPHN-PAEC has led to decreased autophagy and increased in vitro angiogenesis. Inhibition of autophagy also decreased the association between gp91phox and p47phox, NOX activity, and superoxide generation. A nonspecific antioxidant N-acetylcysteine and a NOX inhibitor apocynin decreased autophagy in PPHN-PAEC. In conclusion, autophagy may contribute to impaired angiogenesis in PPHN-PAEC through increasing NOX activity. Our results suggest that, in PPHN-PAEC, a positive feedback relationship

文献 Nature 2008;453, 236-240

TH17に関してよく知られている文献　Nature 453, 236-240, 2008

TGF-βが誘導するFoxp3はRORγtの機能に拮抗することでTH17細胞の分化を抑制する

Liang Zhou1, et al

The Kimmel Center for Biology and Medicine of the Skirball Institute, and,
Howard Hughes Medical Institute, Departments of Microbiology and Pathology, New York University School of Medicine, New York, New York 10016, USA

　IL-17を産生するヘルパーT細胞（Th17細胞）は，マウスで自己免疫を促進することが明らかとされ，現在，ヒトの炎症性疾患の原因になると考えられるようになった。粘膜表面では，Th17細胞は感染から宿主を防御すると考えられており，一方、調節性T（Treg ）細胞は常在微生物叢が引き金となる免疫応答や炎症を制御すると考えられている。この2つのタイプの細胞分化には，トランスフォーミング増殖因子-β（TGF-β）が必要であるが，それぞれ異なる転写因子活性に依存して誘導され，Th17細胞は Rorc(γt) にコードされるRORγtに，Treg 細胞はFoxp3の活性に分化が依存する。相反する活性をもつT細胞の分化をTGF-βがどのように調節するのかを理解は難しい。本論文では，炎症促進性サイトカインと共に，TGF-βが濃度依存的にTh17細胞の分化を調整することを示している。TGF-βは低濃度の場合，IL-6とIL-21との相乗効果によって，IL-23受容体（ IL23R）の発現を促進し，Th17細胞の分化を促す。TGF-βが高濃度の場合は， IL23R の発現が抑制され，Foxp3 + T reg 細胞の分化が促される。さらに，RORγtとFoxp3は，マウスのTGF-βに暴露されたナイーブCD4 + T細胞，および小腸固有層のT細胞の部分集団に共発現している。 in vitro では，TGF-βが誘導するFoxp3はRORγt機能を抑制するが，その機序の少なくとも一部は両者の相互作用を介しているため，この2つの転写因子を共発現する固有層T細胞は，RORγtのみを発現する細胞よりIL-17の産生が少ない。IL-6，IL-21，およびIL-23は，Foxp3を介したRORγtの抑制を解除し，その結果Th17細胞の分化を促進する。したがって，抗原刺激を受けた細胞がTh17細胞あるいはTreg 細胞のどちらに分化するかの決定は，サイトカインが調節するRORγtとFoxp3のバランスに依存するということを本論文では論じている。

基礎論文 NF-kB抑制の追試 J Exp Med 2008;205:1303-15

Divergent roles of endothelial NF-kB in multiple organ injury and bacterial clearance in mouse models of sepsis

Xiaobing Ye, Jianqiang Ding, Xiaozhou Zhou, Guoqian Chen, and Shu Fang Liu
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Feinstein Institute for Medical Research and Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY 11040

　To define the roles of endothelial-intrinsic nuclear factor B (NF-kB) activity in host defense and multiple organ injury in response to sepsis, we generated double transgenic (TG) mice (EC-rtTA/I-Bmt) that conditionally overexpress a degradation-resistant form of the NF-kB inhibitor I-kB (I-kBmt) selectively on vascular endothelium. The EC-rtTA/I-kBmt mice had no basal, but a relatively high level of doxycycline-inducible, I-Bmt expression. I-Bmt expression was detected in endothelial cells, but not in fibroblasts, macrophages, and whole blood cells, confirming that transgene expression was restricted to the endothelium. When subjected to endotoxemia, EC-rtTA/I-kBmt mice showed endothelial-selective blockade of NF-kB activation, repressed expression of multiple endothelial adhesion molecules, reduced neutrophil infiltration into multiple organs, decreased endothelial permeability, ameliorated multiple organ injury, reduced systemic hypotension, and abrogated intravascular coagulation. When subjected to cecal ligation and puncture–induced sepsis, the TG mice had less severe multiple organ injury and improved survival compared with wild-type (WT) mice. WT and EC-rtTA/I-kBmt mice had comparable capacity to clear three different pathogenic bacteria. Our data demonstrate that endothelial NF-kB activity is an essential mediator of septic multiple organ inflammation and injury but plays little role in the host defense response to eradicate invading pathogenic bacteria.

NF-kB活性を血管内皮細胞選択的に抑制すると，白血球系細胞の浸潤が抑制され，血管内皮細胞炎症や多臓器不全が抑制されるが，菌のクリアランスには影響を与えないとする基礎研究論文です。

論文紹介 好中球サンドイッチによる炎症性微小循環障害

Nature Medicine 15, 364 - 366 (2009)


Neutrophil sandwiches injure the microcirculation
Mark R Looney & Michael A Matthay


The systemic and pulmonary microcirculations are the targets of injury in sepsis and acute lung injury, disorders that are major causes of morbidity and mortality in critically ill individuals. Damage to the smallest blood vessels, including arterioles, capillaries and venules, leads to shock, acute respiratory failure and acute renal failure.

Individuals who have sickle cell disease develop occlusion and hypoxia of the microcirculation when challenged with inflammatory insults 1, 2). The microcirculation is also the target of injury from the transfusion of blood products that can produce severe damage to the lung, known as transfusion-related acute lung injury (TRALI). TRALI is estimated to occur in approximately 1 in 5,000 blood transfusions, although it is probably more common, with the lower numbers due to underreporting and other factors 3).

Mouse models of sickle cell disease and TRALI have provided insights into how damage to the microcirculation occurs in response to inflammation. In two such clinically relevant animal models, Hidalgo et al. 4 )now provide insight into how neutrophils respond to acute inflammation and contribute to damage. In this issue of Nature Medicine, the authors show how sequestered neutrophils coordinate tissue injury by interacting with the endothelium, circulating red blood cells and platelets 4). These interactions are mediated through the actions of endothelial E-selectin, neutrophil E-selectin ligand-1 (ESL-1) and the promiscuous leukocyte integrin αMβ2 (also known as CD11b/CD18, Mac-1 and CR 3).

Neutrophils are key sentinel cells of the innate immune system and are the premier cellular responders to acute inflammation. For example, in models of acute lung injury ranging from acid aspiration 5) to ischemia-reperfusion 6) to TRALI 7) , depletion of neutrophils before the injury stimulus protects rabbits, rats and mice, respectively, from lung injury. These noninfectious models differ from the most common clinical causes of acute lung injury, pneumonia and sepsis, in which neutrophils are needed to control the infection. Nonetheless, animal work has demonstrated that the proinflammatory response of the neutrophil can lead to an increase in endothelial and epithelial permeability and, in the case of sepsis, shock and global organ injury 8). Directing the neutrophil responses to combat acute infections without injuring the host remains a lofty goal of modern medicine.

As intrepid responders to acute inflammation, neutrophils are uniquely equipped to mingle with a variety of cells in the microcirculation. To facilitate delivery of neutrophils in the bloodstream to areas of injury and infection, circulating neutrophils marginate along endothelial cells via endothelial E- and P-selectins and their corresponding neutrophil ligands ESL-1, P-selectin glycoprotein ligand-1 and CD44.

Hidalgo et al. 4) provide evidence for neutrophil-platelet or neutrophil–red blood cell interactions in the inflamed systemic microcirculation in the absence of organ injury, findings that imply a possible functional role for the heterotypic aggregates. However, neutrophil-platelet aggregates detected in a mouse model of acid-induced acute lung injury were responsible for organ injury, as blocking these interactions via the P-selectin pathway protected the mice from lung endothelial injury 9).

Using elegant in vivo multichannel fluorescent imaging of the systemic circulation, the authors studied how endothelial cells communicate with neutrophils to stimulate heterotypic interactions with red blood cells and platelets 4). The authors report that ESL-1 on neutrophils, by binding to E-selectin on endothelium, signals the polarized activation of surface αMβ2 integrin on the neutrophil 4).

In a mouse model of sickle cell disease, they show that αMβ2 integrin in turn mediates the heterotypic associations of neutrophils with normal and sickle red blood cells 4); in the TRALI model, αMβ2 integrin mediates the interaction of neutrophils with platelets. The αMβ2 integrin is constitutively present on the neutrophil surface, but inflammation and ESL-1 signaling activates and polarizes it to the leading edge of crawling neutrophils, where the heterophile aggregates form. In the sickle cell model, these events lead to capture of sickle red blood cells and vascular occlusion, and, in the TRALI model, they lead to the capture of platelets and endothelial injury mediated by reactive oxygen species.

These findings are noteworthy and clinically relevant for several reasons. They establish a link between E-selectin–induced regional activation of the neutrophil αMβ2 integrin through ESL-1, a ligand previously not known to transduce signals. The results also expand the function of E-selectin to include the induction of distinct signaling events in neutrophils, adding to its classical role in leukocyte rolling. The E-selectin–ESL-1–αMβ2 integrin pathway has the potential for pharmacologic intervention. Because of its importance in both thrombotic and inflammatory experimental models, this pathway also has the potential for broad relevance in microcirculatory diseases.

Future work is needed to identify the specific ligands on red blood cells and platelets that participate in the heterotypic neutrophil interactions. Targeting platelets in thromboinflammatory diseases is potentially an attractive area of investigation, but it must be carefully tested given the role of platelets in maintaining normal systemic and pulmonary vascular permeability 10). Also needed is an investigation of the dynamic neutrophil–red blood cell and neutrophil-platelet interactions—a circulatory bed that differs substantially from the systemic microcirculation 11). In the lung microcirculation, for example, neutrophils are sequestered by mechanical forces as well as by selectin-mediated mechanisms.

Although pharmacologically disrupting the E-selectin–ESL-1–αMβ2 integrin pathway has the potential to protect against injury to the microcirculation, timing may be key. Lung injury in TRALI, for example, usually manifests maximally within 30–60 minutes after infusion of a blood product and then resolves over the next few days 12). With complications of sickle cell disease, such as acute chest syndrome and vaso-occlusive pain crises, microcirculatory injury is dynamic and will challenge attempts to interrupt the pathway. Investigating whether heterotypic neutrophil interactions are important in subacute or resolving inflammation will be a major goal of future investigations.

References
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2. Gladwin, M.T. & Vichinsky, E. N. Engl. J. Med. 359, 2254–2265 (2008).
3. Toy, P. et al. Crit. Care Med. 33, 721–726 (2005).
4. Hidalgo, A. et al. Nat. Med. 15, 384–391 (2009).
5. Folkesson, H.G., Matthay, M.A., Hebert, C.A. & Broaddus, V.C. J. Clin. Invest. 96, 107–116 (1995).
6. Eppinger, M.J., Deeb, G.M., Bolling, S.F. & Ward, P.A. Am. J. Pathol. 150, 1773–1784 (1997).
7. Looney, M.R., Su, X., Van Ziffle, J.A., Lowell, C.A. & Matthay, M.A. J. Clin. Invest. 116, 1615–1623 (2006).
8. Ware, L.B. & Matthay, M.A. N. Engl. J. Med. 342, 1334–1349 (2000).
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急性肺傷害レビュー Lancet. 2007;369:1553-64

Wheeler AP, Bernard GR.
Acute lung injury and the acute respiratory distress syndrome: a clinical review.
Lancet. 2007 May 5;369(9572):1553-64. Review.

急性肺傷害の総説です。
是非，読まれてみてください。

血小板による炎症増強作用 Circ Res 2007;100:27-40

Platelets as Immune Cells: Bridging Inflammation and Cardiovascular Disease
[Reviews]
von Hundelshausen, Philipp; Weber, Christian

From the Institute of Cardiovascular Molecular Research, University Hospital of the Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Original received September 28, 2006; revision received November 2, 2006; accepted November 6, 2006.
Correspondence to Dr Christian Weber, Institut für Kardiovaskuläre Molekularbiologie, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail cweber@ukaachen.de

Abstract—
Beyond an eminent role in hemostasis and thrombosis, platelets are characterized by expert functions in assisting and modulating inflammatory reactions and immune responses. This is achieved by the regulated expression of adhesive and immune receptors on the platelet surface and by the release of a multitude of secretory products including inflammatory mediators and cytokines, which can mediate the interaction with leukocytes and enhance their recruitment. In addition, platelets are characterized by an enormous surface area and open canalicular system, which in concert with specialized recognition receptors may contribute to the engulfment of serum components, antigens, and pathogens. Platelet-dependent increases in leukocyte adhesion may not only account for an exacerbation of atherosclerosis, for arterial repair processes, but also for lymphocyte trafficking during adaptive immunity and host defense. This review compiles a selection of platelet-derived tools for bridging inflammation and vascular disease and highlights the molecular key components governing platelet-mediated mechanisms operative in immune surveillance, vascular remodeling, and atherosclerosis.


Figure 1. Platelet adhesion molecules and surface receptors. For clarity, the symbols for the various protein domains depicted are explained within the Figure.



Figure 2. Platelet-derived soluble immune mediators. In addition to stimulating signal transduction, shape change, adhesion, and aggregation of platelets, the activation of platelets can result in the release of multiple and diverse soluble mediators with pleiotropic functions in inflammation.



Figure 3. Interactions of platelets with different leukocyte subtypes regulate vascular inflammation. A multitude of molecular mechanisms and platelet-derived components mediate and regulate platelet-induced leukocyte infiltration including chemokine deposition and mononuclear and endothelial cell activation. Depicted are examples of the variety of mechanisms and key elements described in greater detail in the text.