1．総説 Obstructive Sleep Apnea in Infants
Eliot S. Katz, Ron B. Mitchell, and Carolyn M. D'Ambrosio．Am. J. Respir. Crit. Care Med. 2012; 185: 805-816.
Obstructive sleep apnea in infants has a distinctive pathophysiology, natural history, and treatment compared with that of older children and adults. Infants have both anatomical and physiological predispositions toward airway obstruction and gas exchange abnormalities; including a superiorly placed larynx, increased chest wall compliance, ventilation–perfusion mismatching, and ventilatory control instability. Congenital abnormalities of the airway, such as laryngomalacia, hemangiomas, pyriform aperture stenosis, choanal atresia, and laryngeal webs, may also have adverse effects on airway patency. Additional exacerbating factors predisposing infants toward airway collapse include neck flexion, airway secretions, gastroesophageal reflux, and sleep deprivation. Obstructive sleep apnea in infants has been associated with failure to thrive, behavioral deficits, and sudden infant death. The proper interpretation of infant polysomnography requires an understanding of normative data related to gestation and postconceptual age for apnea, arousal, and oxygenation. Direct visualization of the upper airway is an important diagnostic modality in infants with obstructive apnea. Treatment options for infant obstructive sleep apnea are predicated on the underlying etiology, including supraglottoplasty for severe laryngomalacia, mandibular distraction for micrognathia, tonsillectomy and/or adenoidectomy, choanal atresia repair, and/or treatment of gastroesophageal reflux.
2. 原著 A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting
D. Clark Files, Franco R. D'Alessio, Laura F. Johnston, Priya Kesari, Neil R. Aggarwal, Brian T. Garibaldi, Jason R. Mock, Jessica L. Simmers, Antonio DeGorordo, Jared Murdoch, Monte S. Willis, Cam Patterson, Clarke G. Tankersley, Maria L. Messi, Chun Liu, Osvaldo Delbono, J. David Furlow, Sue C. Bodine, Ronald D. Cohn, Landon S. King, and Michael T. Crow. Am. J. Respir. Crit. Care Med. 2012; 185: 825-834.
ALIにおける骨格筋萎縮に関する原著 ポイント：Atrogin-1とMuscle ring finger-1（MuRF-1）のシグナル知識を整理すること
Skeletal muscle weakness is a common finding not only among patients with ALI, but also in patients with other critical illnesses. Clinically apparent weakness is present in 20–50% of patients with critical illness and has been shown to be an independent risk factor for mortality in these patients. A variety of terms have been used in the literature to describe the myopathic weakness in these patients including acute quadriplegic myopathy, critical illness myopathy, and thick filament myopathy, the latter referring to the preferential loss of myosin observed in the muscles of these patients (1–3).
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3.↵ Sher JH, Shafiq SA, Schutta HS. Acute myopathy with selective lysis of myosin filaments. Neurology 1979;29:100–106.
Their data demonstrate that ALI in mice produces marked skeletal muscle wasting and dysfunction similar to that observed in patients with ALI. Muscle wasting and dysfunction in this model is associated with markedly increased NF-κB activity and MuRF1 transcriptional activation and is suppressed by genetic inactivation or biochemical suppression of MuRF1. In contrast, muscle wasting in PF mice is not affected by suppressing MuRF1. It remains to be determined if MuRF1 is expressed in the skeletal muscles of humans with ALI and whether blockade of MuRF1 could prevent muscle wasting in these patients. Although recognizing that the results obtained in the mouse may have limited relevance to ALI in humans, MuRF1 seems to be an attractive therapeutic target for ALI-associated skeletal muscle wasting.
Studies over the last 12 years have defined important roles for muscle-specific genes that regulate muscle wasting in well-defined models of skeletal muscle atrophy, including immobilization, denervation, and hindlimb suspension (4). Prominent among these are the genes Fbx032 (atrogin1 or MAFbx) and Trim63 (muscle ring finger protein-1 [MuRF1]), both of which function as ubiquitin E3 ligases in the proteasome-mediated degradation of skeletal muscle proteins (4, 5). Up-regulation of MuRF1 and atrogin has also been observed in the peripheral muscles of patients with chronic obstructive pulmonary disease and in the diaphragms of mechanically ventilated brain-dead patients (6, 7).
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5. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. Atrogin-1, a muscle- specific f-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 2001;98:14440–14445.
6. Doucet M, Russell A, Léger B, Debigaré R, Joanisse DR, Caron M, LeBlanc P, Maltais F. Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:261–269.
7. Hussain SN, Mofarrahi M, Sigala I, Kim HC, Vassilakopoulos T, Maltais F, Bellenis I, Chaturvedi R, Gottfried SB, Metrakos P, et al. Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med 2010;182:1377–1386.
Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness that persists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown.
Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI.
Methods: Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy–associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporation-mediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALI-associated skeletal muscle wasting.
Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associated with reduced muscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed.
Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury in ALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.
3. 原著 Activation of Mitochondrial Biogenesis by Heme Oxygenase-1–mediated NF-E2–related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis
Nancy Chou MacGarvey, Hagir B. Suliman, Raquel R. Bartz, Ping Fu, Crystal M. Withers, Karen E. Welty-Wolf, and Claude A. Piantadosi．Am. J. Respir. Crit. Care Med. 2012; 185: 851-861.
ポイント：AKt-1 KOマウスの使用，Nrf2 KOマウスの使用，S.aureus生菌敗血症モデル，His3 as a nuclear reference protein
Studies were preapproved by our Institutional Animal Care and Use Committee. C57Bl6/J (WT) mice were obtained from Jackson Laboratory (Bar Harbor, ME). Nrf2－/－ mice (Riken, Saitama, Japan) and Akt1－/－ mice (Jackson) were bred institutionally and both sexes used at 9–15 weeks of age.
In C57BL/6J mice (WT), sepsis induced by implanting fibrin clots containing live 5 × 107 cfu S. aureus into the peritoneum followed by fluid resuscitation produces dose-dependent organ damage and lethality .
Haden DW, Suliman HB, Carraway MS, Welty-Wolf KE, Ali AS, Shitara H, Yonekawa H, Piantadosi CA. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med 2007;176:768–777.
Hmox1 is thought to protect against sepsis-induced tissue damage, and it is induced by multiple transcriptional elements that respond to inflammation, especially the basic leucine zipper transcription factor, NF-E2 related factor-2 (Nrf2) (1). Nrf2 is normally sequestered in the cytosol by the cysteine-rich Kelch-like ECH-associated protein 1 (2), and Kelch-like ECH-associated protein 1 oxidation allows Nrf2 nuclear translocation (3) and binding to antioxidant response element (ARE) motifs located 5′ to the Hmox-1 transcription start site (4). Nrf2 also occupies activating ARE motifs in the nuclear respiratory factor-1 (NRF-1) promoter, and under the influence of CO, Nrf2 and NRF-1 along with NRF-2 (Gabpa) and the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 coactivators stimulate mitochondrial biogenesis (5). Nrf2 also influences the innate immune response and survival in cecal ligation and puncture (6) and modulates leukocyte function in sepsis (7).
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7.↵ Kong X, Thimmulappa R, Craciun F, Harvey C, Singh A, Kombairaju P, Reddy SP, Remick D, Biswal S. Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. Am J Respir Crit Care Med 2011;184:928–938.
4. To the Editor: 敗血症病態におけるアドレナリン作動性β-受容体活性について
Michael Eisenhut
Inflammation-induced Desensitization of β-Receptors in Acute Lung Injury
Am. J. Respir. Crit. Care Med. 2012; 185: 894
The authors of a randomized controlled trial of the inhaled β-agonist albuterol in patients with acute lung injury mentioned as reasons for a failure to improve outcome poor delivery, damage to alveolar epithelium, down-regulation of β2-receptors, possible differences in genetic variants of the β-receptor in the groups of the trial, and the possibility that fluid clearance was already maximized by lung-protective ventilation and a fluid-conservative hemodynamic strategy (1). The authors did not consider an important phenomenon observed in patients with severe systemic inflammatory response syndromes, who constituted the majority in this trial. It is a reduced responsiveness of β-receptors to β-agonist induced by inflammatory mediators.
Regarding this reduced responsiveness of β-receptors in a systemic inflammatory response, most can be learned from previous research into induction of β2-receptor hyporesponsiveness in models of asthma and airway smooth muscle cells. One mechanism is desensitization by cytokines including nterleukin-1β (IL-1), tumor necrosis factor, transforming growth factor-β, and IL-13 (2). In human airway smooth muscle cells, IL-1 induces cyclooxygenase-2 (COX-2) expression and hence prostaglandin E2 (PGE2). PGE2 causes cAMP formation, and it has been shown that protein kinase A (PKA) activated by cAMP can phosphorylate the β2-adrenoceptor and induce desensitization of the receptor by interference with its attachment with G protein (3). PKA has also been shown to down-regulate β2-receptors by inhibition of transcription and was found to activate phosphodiesterase-4, which reduces cAMP levels (4). IL-1–mediated activation of the Gi pathway by up-regulation of inhibitory G proteins Giα1, Giα2, and Giα3 causes uncoupling of the β-adrenergic receptors from the adenylate cyclase (5).
Another avenue for rapid desensitization of the β2-receptor has been discovered in a rat model, where IL-1 elevated intracellular G protein–coupled receptor kinase-2 (GRK2), an enzyme that was detected in rat alveolar epithelial cells (6) and is the key enzyme in rapid desensitization of β2-receptors to endogenous and exogenous catecholamines.
Dexamethasone has been shown to prevent this IL-1–induced up-regulation of GRK-2 levels (5). Dexamethasone also inhibits IL-1β–induced COX-2 expression and PGE2 release (3).
Future research into pathways to improve the outcome of lung injury with β-agonists needs to explore the regulation of β-agonist sensitivity in human alveolar epithelial cells in vitro. β-Agonists may improve outcome of lung injury if their receptors are (hyper-) sensitized by systemic or local application of corticosteroids.
1.↵ The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized beta 2-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;184:561–568. Abstract/FREE Full Text
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Michael A. Matthay, B. Taylor Thompson, and Roy Brower
Inflammation-induced Desensitization of β-Receptors in Acute Lung Injury
Am. J. Respir. Crit. Care Med. 2012; 185: 894-895
We appreciate the thoughtful comments by Dr. Eisenhut regarding potential additional explanations for why the aerosolized β2-agonist albuterol was not effective in improving clinical outcomes in our phase III clinical trial in patients with acute lung injury (1). We agree that proinflammatory substances such as IL-1 may decrease the capacity of alveolar epithelial cells to clear alveolar edema fluid (2). Dr. Eisenhut notes that there is experimental evidence that dexamethasone might be effective in preventing IL-1–dependent desensitization of β2-receptors to catecholamines. Further, he proposes that β-agonists might improve the outcome of lung injury if the receptors were hypersensitized by systemic or local application of corticosteroids.
A rigorous assessment of combined β-agonist and corticosteroid therapy would require a careful pre-clinical assessment followed by well-designed clinical trials. The initial clinical studies would need a strong focus on safety, especially because of the recently published BALTI-2 trial with intravenous albuterol, indicating harmful effects with β-agonist monotherapy (3). In addition, assays of glucocorticoid responsiveness demonstrate considerable variability among normal individuals and among patients with various clinical diseases. There are several explanations for this variability; some of it may be attributed to genetic variations in the glucocorticoid receptor (4), but some of the variability may be attributable to the effects of the inflammatory environment (5–8).
1.↵ National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized beta-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;184:561–568. Abstract/FREE Full Text
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6. Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and t cell response to glucocorticoids. J Immunol 1993;151:3460–3466. Abstract
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8.↵ Meduri GU, Yates CR. Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS. Ann N Y Acad Sci 2004;1024:24–53. CrossRefMedline
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