Editorials
However, the impact of this study should be interpreted in the context of current science of pericardiopulmonary arrest care; these flndings add to the fabric of understanding that meticulous attention to all aspects of CPA care may improve outcomes. The work by Topjian et al's (9) reminds us that although we work on a novel therapy for patients with CPA, we should pay attention to the details of therapies we have.
REFERENCES 1. Matos RI, Watson RS, Nadkarni VM, et al; American Heart Association's Get With The Guidelines-Resuscitation (Formerly the National Registry of Cardiopulmonary Resuscitation) Investigators: Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pédiatrie cardiac arrests. Circulation 2013; 127:442-451 2. Girotra S, Spertus JA, Li Y, et al; American Heart Association Get With the Guidelines-Resuscitation Investigators: Survival trends in pédiatrie in-hospital cardiac arrests: An analysis from Get With the Guidelines-Resuscitation. C/rc Oardiovasc Oual Outcomes 2013; 6:42-49 3. Samson RA, Nadkarni VM, Meaney PA, et al; American Heart Association National Registry of CPR Investigators: Outcomes of in-hospital ventricular fibrillation in children. N EngI J Med 2006; 354:2328-2339 4. Sutton RM, Niles D, Nysaether J, et al: Quantitative analysis of CPR quality during in-hospital resuscitation of older children and adolescents. Pediatrics 2009; 124:494-499
5. Sutton RM, French B, Nishisaki A, et al: American Heart Association cardiopulmonary resuscitation quality targets are associated with improved arterial blood pressure during pédiatrie cardiac arrest. Resuscitation 2013; 84:168-172 6. Edelson DP, Abella BS, Kramer-Johansen J, et al: Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation 2006; 71:137-145 7 Idris AH, Guffey D, Aufderheide TP, et al; Resuscitation Outcomes Consortium (ROC) Investigators: Relationship between chest compression rates and outcomes from cardiac arrest. Circulation 2012; 125:3004-3012 8. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: Pédiatrie advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergeney Cardiovaseular Care. Circulation 2010; 122:S876-S908 9. Topjian AA, Freneh B, Sutton RM, et al: Early Postresuseitation Hypotension Is Associated With Increased Mortality Following Pédiatrie Cardiac Arrest. Crit Care Med 2014; 42:1518-1523 10. Lee JK, Brady KM, Mytar JO, et al: Cerebral blood flow and cerebrovascular autoregulation in a swine model of pédiatrie eardiae arrest and hypothermia. Crit Care Med 2011 ; 39:2337-2345 11. Sundgreen C, Larsen FS, Herzog TM, et al: Autoregulation of eerebral blood flow in patients resuseitated from cardiac arrest. Stroke 2001 ; 32:128-132 12. Pigula FA, Wald SL, Shackford SR, et al: The eftect of hypotension and hypoxia on children with severe head injuries. J Pediatr Surg 1993; 28:310-314; discussion 315 13. Vavilala MS, Bowen A, Lam AM, et al: Blood pressure and outcome after severe pédiatrie traumatic brain injury. J Trauma 2003; 55:1039-1044
Nitric Oxide Synthase and Vascular Dysfunction in Sepsis: Should We Target Nitric Oxide Synthase 1, Nitric Oxide Synthase 2, Both, or Neither?* Mitchell P. Fink, MD Department of Surgery; and Department of Anesthesiology David Geffen School of Medicine at UCLA Los Angeles, CA
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ogether with carbon monoxide and hydrogen sulfide, nitric oxide (NO) is recognized as being one of three gaseous molecules that play important roles as signaling agents in mammalian biology. NO is generated in cells via a reaction that uses the amino acid L-arginine and molecular oxygen as substrates. This reaction is catalyzed by a family of enzymes called "nitric oxide synthases" (NOSs). Three NOS
'See also p. e39i. Keywords: 7-nitroindazole; guanylyl cyclase; lipopolysaccharide; vasoplegia The author has disclosed that he does not have any potential eonflicts of Interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.00000000000003SS
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isoforms are known: NOSl (neuronal NOS); NOS2 (inducible NOS); and N0S3 (endothelial NOS). The enzymatic activity of NOSl and NOS3 is controlled by changes in intracellular calcium ion (Ca^+) concentration. By contrast, the enzymatic activity of NOS2 is independent of Ca'^ concentration. NOSl and N0S3 are expressed constitutively although the expression of these proteins can be up-regulated under certain conditions (1, 2). NOS2 is an inducible protein and its expression in macrophages and other cell types can be triggered by various proinflammatory mediators. N0S3-dependent production of NO in endothelial cells promotes dilation of resistance and capacitance blood vessels (3). This process depends on diffusion of NO from the endothelium into nearby vascular smooth cells wherein a heme-containing enzyme, soluble guanylyl cyclase, is activated by the formation of a chemical bond between the diatomic gas and an iron atom, which is in the -1-2 (ferrous) oxidation state, in the heme moiety. After being activated, soluble guanylyl cyclase catalyzes the conversion of the purine nucleotide, guanosine triphosphate, into 3',5'-cyclic guanosine monophosphate (cCMP). This "second messenger" activates a protein June 2014 • Volume 42 • Number 6
Editorials kinase that leads to the phosphorylation of key target proteins, ultimately leading to reduced Ca'^ concentration in the cytosol of vascular smooth muscle cells as well as decreased sensitivity to Ca^+ of the contractile system in these cells. This chain of events results in diminished vasomotor tone and is supported by other NO- or cGMP-dependent events, such as activation of potassium channels and subsequent membrane hyperpolarization (4, 5). N0S3 is not the only NOS isoform that can participate in the regulation—or dysregulation—of vasomotor tone. When rodents are injected with large doses of lipopolysaccharide (LPS), the animals develop systemic arterial hypotension and "vasoplegia" (i.e., resistance to the pressor effects of vasoconstricting compounds, such as norepinephrine). Similar findings are observed when mice or rats are subjected to cecal ligation and perforation (CLP) to induce polymicrobial peritonitis. These circulatory system changes are mediated, at least in part, by increased production of NO in vascular smooth muscle cells as a result of up-regulated expression of N0S2 in these cells (6-9). Excess NO production has been implicated as being a factor in the pathophysiology systemic arterial hypotension and vasoplegia in patients with septic shock (10-13). Eurthermore, evidence has been presented to support the view that N0S2 expression is up-regulated in vascular smooth muscle samples from septic shock patients (14, 15). Still, the notion that N0S2-derived NO is a key mediator of hypotension and vasoplegia in septic patients is not yet supported by bullet-proof evidence, and data have been published that call this concept into question (16).
Because of the disappointing results in these clinical trials, there seems to be little enthusiasm at present for developing pharmacological agents that target excessive NO production as treatment of septic shock (or other shock states that are associated with decreased systemic vascular resistance and vasoplegia). But, maybe, our approach has been wrong. L-NMMA inhibits all three NOS isoforms and PHP scavenges NO irrespective of whether the gaseous molecule was produced by one or more of the NOS isoforms or even the nonenzymatic reduction of nitrite anion (NO^") derived from dietary or other sources. These nonselective pharmacological approaches for targeting "excessive" NO production likely impair normal regulation of microcircuiatory perfusion. Eurthermore, these approaches can promote or exacerbate pulmonary hypertension, leading to or worsening right ventricular failure.
A more appealing pharmacological approach might be to inhibit (only) the "correct" NOS isoform, that is, the isoform that is most responsible for promoting deranged cardiovascular function in patients with septic shock. Until fairly recently, most scientists and clinical investigators, who are interested in the pathogenesis and treatment of septic shock, likely would have expressed the view that, among the NOS isoforms, NOS2 is the most appropriate drug target. Certainly, there are data from studies using rodent (22-28) or ovine (29, 30) models of sepsis that lend support to this view. By the same token, however, there are also data in the literature that suggest that selectively inhibiting NOS2 might worsen mortality due to sepsis (31). Could it be that NOSl is a more suitable target? Prompted by idea that excessive production of NO conNOSl was originally identified in rat brain (32, 33), but it tributes to the pathogenesis of circulatory shock, investigators is now recognized that NOSl is found in many different cell have carried out two large, multicentric, placebo-controlled, types, including skeletal muscle cells (34), cardiac myocytes randomized, clinical trials of the isoform nonselective NOS (35, 36), vascular smooth muscle cells (37, 38), and renal macinhibitor, N''-monomethyl-L-arginine ( L - N M M A ) . The first ula densa cells (39). Human NOSl is encoded by a gene located of these trials enrolled patients with septic shock and was on chromosome 12, and several splice variants have been stopped early because of excess mortality among the patients described (40). Some data suggest that a NOSl splice variant randomized to treatment with L - N M M A (17). The second of can be found in mitochondria (41) although the existence and these trials enrolled patients with acute myocardial infarction identity of the putative mitochondrial NOS remains quite concomplicated by cardiogenic shock and was stopped early on troversial (40,42). the basis of a prespecified futility analysis (18). The notion that NOSl might be a key player in the pathophysiology of sepsis probably dates back to work by el-Dwairi Another approach for targeting excessive NO production as a way to ameliorate shock was also evaluated in a large, et al (43), who showed that expression of all three NOS isoforms was up-regulated in skeletal muscle when rats were multicentric, randomized controlled trial. This approach was challenged with LPS. Interest in NOSl as an important gene based on extensive data, showing that hemoglobin effectively product in sepsis and related conditions was enhanced by a scavenges NO (19). In a phase 2 trial, pyridoxalated hemogloseries of articles from Daniel Traber's laboratory in Galveston, bin polyoxyethylene (PHP), a chemically modified cell-free Texas. Eor example, Westphal et al (44) reported that treatment form of human hemoglobin, was shown to ameliorate hypotension and decrease vasopressor requirements in patients with 7-nitroindazole (7-NI), a relatively isoform-selective NOSl antagonist, ameliorated myocardial dysfunction and with distributive (i.e., vasoplegic) shock (20). This preliminary study was followed by a large, multicentric, phase 3 pulmonary edema in sheep subjected to combined burn and smoke inhalation injury. Using the same ovine model, Saunrandomized clinical trial of PHP in patients with distributive shock. The primary endpoint was all-cause mortality at 28 ders et al (45) showed that treatment with 7-NI ameliorated oxidative and nitrosative stress in pulmonary tissue. Lange days after enrollment. The trial was terminated early after the et al (46) employed an ovine model of Pseudomonas aeruginosa third interim analysis of results because the number of deaths pneumonia and showed that treatment with 7-NI ameliorated in the PHP cohort exceeds the number of deaths in the plasystemic arterial hypotension and increased systemic vascular cebo cohort (21). Critical Care Medicine
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Editorials resistance. Treatment with 7-NI was associated with other salutary effects, such as amelioration of hepatocellular injury and metabolic acidosis. Now, in this issue of Critical Care Medicine, Nardi et al (47) have added important information about the role of NOSl in the pathogenesis of circulatory dysfunction in sepsis. These authors studied septic rats. Sepsis was induced by performing a procedure called "CLP" that induces polymicrobial bacterial peritonitis. When the animals were studied 24 hours after the induction of sepsis, treatment with 7-NI or S-methyl-L-thiocitrulline, a potent isoform-selective NOSl inhibitor that is chemically distinct from 7-NI, significantly augmented the pressor response to infusion of norepinephrine. Importantly, the authors showed that sepsis was associated with increased NOSl expression in the wall of the aorta and mesenteric blood vessels. The data obtained by Nardi et al (47) support the view that NOSl may be an attractive drug target as scientists and clinical investigators seek to develop agents to ameliorate circulatory dysfunction in patients with septic shock. Great caution should be exercised in this regard, however, in view of findings that were reported several years ago by Cui et al (48). These investigators subjected wild-type (WT) and NOSl "knockout" (KO) mice (i.e., mice with a genetic deficiency of NOSl) to CLP. Some WT mice were treated with 7-Nl. Sepsis-induced mortality was significantly greater for NOSl KO mice compared with WT mice. Similarly, when septic WT mice were treated with 7-NI, mortality was increased significantly. The mechanism(s) responsible for the deleterious effects of genetic or pharmacological ablation of NOSl-dependent signaling on survival were not elucidated. Nevertheless, circulating levels of certain proinflammatory cytokines were greater in septic NOSl KO mice compared with septic WT mice, suggesting that NOSl-dependent NO production may be important for controlling the inflammatory response to infection. In summary, the true role of NOSl in sepsis remains to be delineated. Some findings suggest that inhibiting this enzyme could be beneficial, whereas other data suggest that this strategy might be deleterious. Additional preclinical studies are clearly warranted.
REFERENCES 1. Garthwaite J, Boulton CL: Nitric oxide signaling in the central nervous system. Annu Rev Physiol 1995; 57:683-706 2. Kroll J, Waltenberger J: VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Bioehem Biophys Res Commun 1998; 252:743-746 3. Bauer V, Sotníková R: Nitric oxide-The endothelium-derived relaxing factor and its role in endothelial functions. Gen Physiol Biophys 2010; 29:319-340 4. Bolotina VM, Najibi S, Palacino JJ, et al: Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1 994; 368:850-853 5. Archer SL, Huang JM, HampI V, et al: Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proe Nati Aead Sei USA 1994; 91:7583-7587 6. Hoque AM, Papapetropoulos A, Venema RC, et al: Effects of antisense oligonucleotide to iNOS on hemodynamic and vascular changes induced by LPS. Am J Physiol 1998; 275:H1078-H1 083
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7 Klein SM, Wong HR, Dayao EK, et al: Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, inos mrna expression and NF-kappaB nuclear translocation in rats. Shock 2000; 14:544-549 8. Wheeler DS, Lahni PM, Hake PW, et al: The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis. Shock 2007; 28:353-359 9. Hollenberg SM, Broussard M, Osman J, et al: Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res 2000; 86:774-778 10. Tsuneyoshi I, Kanmura Y, Yoshimura N: Nitric oxide as a mediator of reduced arterial responsiveness in septic patients. Crit Care Med 1996; 24:1083-1086 11. Avontuur JA, Tutein Nolthenius RP, Buijk SL, et al: Effect of L-NAME, an inhibitor of nitric oxide synthesis, on cardiopulmonary function in human septic shock. Chest 1998; 113:1640-1646 1 2. Kiehl MG, Ostermann H, Meyer J, et al: Nitric oxide synthase inhibition by L-NAME in leukocytopenic patients with severe septic shock. Intensive Care Med 1997; 23:561-566 13. Grover R, Zaccardelli D, Colice G, et al: An open-label dose escalation study of the nitric oxide synthase inhibitor, A/(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo VVellcome International Septic Shock Study Group. Crit Care Med 1999; 27:913-922 14. Stoclet JC, Martinez MC, Ohimann P, et al: Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock. Circulation 1999; 100:107-112 15. Annane D, Sanquer S, Sébille V, et al: Compartmentalised inducible nitric-oxide synthase activity in septic shock. Lancet 2000; 355:1143-1148 16. Reade MC, Millo JL, Young JD, et al: Nitric oxide synthase is downregulated, while haem oxygenase is increased, in patients with septic shock. BrJ Anaesth 2005; 94:468-473 17. López A, Lorente JA, Steingrub J, et al: Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock. Crit Care Med 2004; 32:21-30 18. Alexander JH, Reynolds HR, Stebbins AL, et al; TRIUMPH Investigators: Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: The TRIUMPH randomized controlled trial. JAMA 2007; 297:1657-1666 19. Doherty DH, Doyle MP, Curry SR, et al: Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat Bioteehnol 1998; 16:672-676 20. Kinasewitz GT, Privalle CT, Imm A, et al: Muiticenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock. Crit Care Med 2008; 36:1999-2007 21. Curacyte Health Sciences press release. Munich. Available at: http:// www.curacyte.eu/press_releases.htm. Accessed August, 26, 2011 22. Xie XO, Shinozawa Y, Sasaki J, et al: The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model. J Surg Res 2008; 146:298-303 23. Astolfi RS, Khouri DG, Brandizzi LI, et al: Antagonic effect of the inhibition of inducible nitric oxide on the mortality of mice acutely infected with Escherichia coli and Bacteroides fragilis. Braz J Med Biol Res 2007; 40:317-322 24. Strunk V, Hahnenkamp K, Schneuing M, et al: Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 2001; 92:681-687 25. Wu CC, Chen SJ, Szabó C, et al: Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 1995; 114:1666-1672 26. Lehner MD, Marx D, Boer R, et al: In vivo characterization of the novel imidazopyridine BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]3H-imidazo[4,5-b]pyridine], a potent and highly selective inhibitor of inducible nitric-oxide synthase. J Pharmacol Exp Ther 2006; 317:181-187 June 2014 • Volume 42 • Number 6
Editorials 27 Zheng Y, Lee S, Liang X, et al: Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice. J Infect Dis 2013; 208:1803-1812 28. Aranow JS, Zhuang J, Wang H, et al: A selective inhibitor of inducible in nitric oxide synthase prolongs survival in a rat model of bacterial peritonitis: Comparison with two nonseiective strategies. Shock 1996; 5:116-121 29. Su F, Huang H, Akieda K, et al: Ettects ot a selective iNOS inhibitor versus norepinephrine in the treatment ot septic shock. Shock 2010; 34:243-249 30. Lange M, Hamahata A, Traber DL, et al: Specitie inhibition ot nitric oxide synthases at ditterent time points in a murine model ot pulmonary sepsis. Biochem Biophys Res Commun 2011 ; 404:877-881 31. Cobb JP, Hotehkiss RS, Swanson PE, et al: Indueible nitrie oxide synthase (iNOS) gene detieieney inereases the mortality of sepsis in miee. Surgery 1999; 1 26:438-442 32. Knowles RG, Palaeios M, Palmer RM, et al: Formation of nitrie oxide trom L-arginine in the eentral nervous system: A transduetion mechanism tor stimulation ot the soluble guanylate cyclase. Proc Nati Acad Sei USA1989; 86:5159-5162 33. Bredt DS, Snyder SH: Isolation ot nitric oxide synthetase, a calmodulinrequiring enzyme. Proc Nati Acad Sei USAI 990; 87:682-685 34. Kobzik L, Reid MB, Bredt DS, et al: Nitric oxide in skeletal muscle. Nature 1994; 372:546-548 35. Xu KY, Huso DL, Dawson TM, et al: Nitric oxide synthase in cardiac sareoplasmie retieulum. Proc Nati Acad Sei USA 1999; 96:657-662 36. Ashley EA, Sears CE, Bryant SM, et al: Cardiae nitrie oxide synthase 1 regulates basal and beta-adrenergie contractility in murine ventricular myocytes. Circulation 2002; 1 05:3011 -3016 37. Papadaki M, Tilton RG, Eskin SG, et al: Nitric oxide production by cultured human aortic smooth muscle cells: Stimulation by tluid tlow. Am J Physioi 1998; 274:H61 6-H626 38. Schwarz PM, Kleinert H, Förstermann U: Potential tunctional significance of brain-type and muscle-type nitrie oxide synthase I expressed
in adventitia and media of rat aorta. Arterioscler Thromb Vase Biol 1999; 19:2584-2590 39. Wileox CS, Weleh WJ, Murad F, et al: Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Nati Acad Sei U SA 1992; 89:11993-11997 40. Tengan CH, Rodrigues GS, Godinho RO: Nitrie oxide in skeletal muscle: Role on mitochondrial biogenesis and tunction. Int J Mol Sei 2012; 13:17160-17184 41. Kanai AJ, Pearce LL, Clemens PR, et al: Identitication of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. Proc Nati Acad Sei USA 2001 ; 98:14126-14131 42. Tay YM, Lim KS, Sheu FS, et al: Do mitochondria make nitrie oxide? No? Free Radie Res 2004; 38:591-599 43. el-Dwairi Q, Comtois A, Guo Y, et al: Endotoxin-indueed skeletal muselé eontraetile dysfunetion: Contribution of nitrie oxide synthases. Am J Physiol 1 998; 274:C770-C779 44. Westphal M, Enkhbaatar P, Sehmalstieg FC, et al: Neuronal nitrie oxide synthase inhibition attenuates cardiopulmonary dystunctions after combined burn and smoke inhalation injury in sheep. Crit Care Med 2008; 36:1196-1 204 45. Saunders FD, Westphal M, Enkhbaatar P, et al: Molecular biological effects ot selective neuronal nitrie oxide synthase inhibition in ovine lung injury. Am J Physiol Lung Cell Mol Physioi 2010; 298:L427-L436 46. Lange M, Hamahata A, Traber DL, et al: Etteets ot early neuronal and delayed indueible nitrie oxide synthase bloekade on cardiovascular, renal, and hepatic function in ovine sepsis. Anesthesiology 2010; 113:1376-1384 47 Nardi GM, Scheschowitsch K, Ammar D, et al: Neuronal Nitric Oxide Synthase and Its Interaction With Soluble Guanylyl Cyclase Is a Key Factor tor the Vascular Dystunction of Experimental Sepsis. Crit Care Med 2014; 42:e391-e400 48. Cui X, Besch V, Khaibullina A, et al: Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis. intensive Care Med 2007; 33:1 993-2003
Our Natural Defense: The SkinP Jeremy Goverman, MD, FACS Division of Burns Massachusetts General Hospital Boston, MA
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n the modern burn ICU, sepsis is attributed to the majority of late deaths after large thermal injury (1-3). Impaired immune function is noted in such patients, the etiology of which is multifactorial, and likely contributes to these deaths (4). Additionally, most of these deaths involve multiple drugresistant microorganisms. The day when Colistin may actually be the appropriate empiric therapy, in at least one burn hospital, is upon us (5); however, traditional antimicrobials 'See also p. e420. Key Words: antimicrobial peptides; barrier tunction; burn; permeability barrier; stratum corneum The author has disclosed that he does not have any potential conflicts ot interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI:10.1097/CCM.0000000000000356
Crifical Care Medicine
will never be a permanent solution to this problem. A more detailed understanding of the host response to burn injury may lead to the development of novel methods of treatment. The skin and its response to injury represent an important area of such research. In this issue of Critical Care Medicine, Plichta et al (6) demonstrate localized and systemic alterations in epithelial barrier function utilizing a murine scald burn model. This work builds on previous research that has shown a number of altered defensive mechanisms present within, and surrounding, burn tissue (7-9). The ability to repair and augment these mechanisms may lead to improvements in burn care. Over the past 10-15 years, researchers have uncovered the complex orchestration of defensive events taking place within our skin, at baseline, and in response to barrier disruption (10-12). The epidermis is a protective, proinflammatory, immune organ, and the majority of its defensive actions take place within the stratum corneum (SC). The SC is made up of two components: cellular (lipid deplete corneocytes) and extracellular (lipid-rich matrix). Each component plays critical and overlapping roles in defending humans from cutaneous microbial invasion. SC defense can be categorized into three areas: 1) a physical barrier; 2) a generator of antimicrobial lipids, peptides, toU-like receptors www.ccmjournal.org
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However, the impact of this study should be interpreted in the context of current science of pericardiopulmonary arrest care; these flndings add to the fabric of understanding that meticulous attention to all aspects of CPA care may improve outcomes. The work by Topjian et al's (9) reminds us that although we work on a novel therapy for patients with CPA, we should pay attention to the details of therapies we have.
REFERENCES 1. Matos RI, Watson RS, Nadkarni VM, et al; American Heart Association's Get With The Guidelines-Resuscitation (Formerly the National Registry of Cardiopulmonary Resuscitation) Investigators: Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pédiatrie cardiac arrests. Circulation 2013; 127:442-451 2. Girotra S, Spertus JA, Li Y, et al; American Heart Association Get With the Guidelines-Resuscitation Investigators: Survival trends in pédiatrie in-hospital cardiac arrests: An analysis from Get With the Guidelines-Resuscitation. C/rc Oardiovasc Oual Outcomes 2013; 6:42-49 3. Samson RA, Nadkarni VM, Meaney PA, et al; American Heart Association National Registry of CPR Investigators: Outcomes of in-hospital ventricular fibrillation in children. N EngI J Med 2006; 354:2328-2339 4. Sutton RM, Niles D, Nysaether J, et al: Quantitative analysis of CPR quality during in-hospital resuscitation of older children and adolescents. Pediatrics 2009; 124:494-499
5. Sutton RM, French B, Nishisaki A, et al: American Heart Association cardiopulmonary resuscitation quality targets are associated with improved arterial blood pressure during pédiatrie cardiac arrest. Resuscitation 2013; 84:168-172 6. Edelson DP, Abella BS, Kramer-Johansen J, et al: Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation 2006; 71:137-145 7 Idris AH, Guffey D, Aufderheide TP, et al; Resuscitation Outcomes Consortium (ROC) Investigators: Relationship between chest compression rates and outcomes from cardiac arrest. Circulation 2012; 125:3004-3012 8. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: Pédiatrie advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergeney Cardiovaseular Care. Circulation 2010; 122:S876-S908 9. Topjian AA, Freneh B, Sutton RM, et al: Early Postresuseitation Hypotension Is Associated With Increased Mortality Following Pédiatrie Cardiac Arrest. Crit Care Med 2014; 42:1518-1523 10. Lee JK, Brady KM, Mytar JO, et al: Cerebral blood flow and cerebrovascular autoregulation in a swine model of pédiatrie eardiae arrest and hypothermia. Crit Care Med 2011 ; 39:2337-2345 11. Sundgreen C, Larsen FS, Herzog TM, et al: Autoregulation of eerebral blood flow in patients resuseitated from cardiac arrest. Stroke 2001 ; 32:128-132 12. Pigula FA, Wald SL, Shackford SR, et al: The eftect of hypotension and hypoxia on children with severe head injuries. J Pediatr Surg 1993; 28:310-314; discussion 315 13. Vavilala MS, Bowen A, Lam AM, et al: Blood pressure and outcome after severe pédiatrie traumatic brain injury. J Trauma 2003; 55:1039-1044
Nitric Oxide Synthase and Vascular Dysfunction in Sepsis: Should We Target Nitric Oxide Synthase 1, Nitric Oxide Synthase 2, Both, or Neither?* Mitchell P. Fink, MD Department of Surgery; and Department of Anesthesiology David Geffen School of Medicine at UCLA Los Angeles, CA
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ogether with carbon monoxide and hydrogen sulfide, nitric oxide (NO) is recognized as being one of three gaseous molecules that play important roles as signaling agents in mammalian biology. NO is generated in cells via a reaction that uses the amino acid L-arginine and molecular oxygen as substrates. This reaction is catalyzed by a family of enzymes called "nitric oxide synthases" (NOSs). Three NOS
'See also p. e39i. Keywords: 7-nitroindazole; guanylyl cyclase; lipopolysaccharide; vasoplegia The author has disclosed that he does not have any potential eonflicts of Interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.00000000000003SS
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isoforms are known: NOSl (neuronal NOS); NOS2 (inducible NOS); and N0S3 (endothelial NOS). The enzymatic activity of NOSl and NOS3 is controlled by changes in intracellular calcium ion (Ca^+) concentration. By contrast, the enzymatic activity of NOS2 is independent of Ca'^ concentration. NOSl and N0S3 are expressed constitutively although the expression of these proteins can be up-regulated under certain conditions (1, 2). NOS2 is an inducible protein and its expression in macrophages and other cell types can be triggered by various proinflammatory mediators. N0S3-dependent production of NO in endothelial cells promotes dilation of resistance and capacitance blood vessels (3). This process depends on diffusion of NO from the endothelium into nearby vascular smooth cells wherein a heme-containing enzyme, soluble guanylyl cyclase, is activated by the formation of a chemical bond between the diatomic gas and an iron atom, which is in the -1-2 (ferrous) oxidation state, in the heme moiety. After being activated, soluble guanylyl cyclase catalyzes the conversion of the purine nucleotide, guanosine triphosphate, into 3',5'-cyclic guanosine monophosphate (cCMP). This "second messenger" activates a protein June 2014 • Volume 42 • Number 6
Editorials kinase that leads to the phosphorylation of key target proteins, ultimately leading to reduced Ca'^ concentration in the cytosol of vascular smooth muscle cells as well as decreased sensitivity to Ca^+ of the contractile system in these cells. This chain of events results in diminished vasomotor tone and is supported by other NO- or cGMP-dependent events, such as activation of potassium channels and subsequent membrane hyperpolarization (4, 5). N0S3 is not the only NOS isoform that can participate in the regulation—or dysregulation—of vasomotor tone. When rodents are injected with large doses of lipopolysaccharide (LPS), the animals develop systemic arterial hypotension and "vasoplegia" (i.e., resistance to the pressor effects of vasoconstricting compounds, such as norepinephrine). Similar findings are observed when mice or rats are subjected to cecal ligation and perforation (CLP) to induce polymicrobial peritonitis. These circulatory system changes are mediated, at least in part, by increased production of NO in vascular smooth muscle cells as a result of up-regulated expression of N0S2 in these cells (6-9). Excess NO production has been implicated as being a factor in the pathophysiology systemic arterial hypotension and vasoplegia in patients with septic shock (10-13). Eurthermore, evidence has been presented to support the view that N0S2 expression is up-regulated in vascular smooth muscle samples from septic shock patients (14, 15). Still, the notion that N0S2-derived NO is a key mediator of hypotension and vasoplegia in septic patients is not yet supported by bullet-proof evidence, and data have been published that call this concept into question (16).
Because of the disappointing results in these clinical trials, there seems to be little enthusiasm at present for developing pharmacological agents that target excessive NO production as treatment of septic shock (or other shock states that are associated with decreased systemic vascular resistance and vasoplegia). But, maybe, our approach has been wrong. L-NMMA inhibits all three NOS isoforms and PHP scavenges NO irrespective of whether the gaseous molecule was produced by one or more of the NOS isoforms or even the nonenzymatic reduction of nitrite anion (NO^") derived from dietary or other sources. These nonselective pharmacological approaches for targeting "excessive" NO production likely impair normal regulation of microcircuiatory perfusion. Eurthermore, these approaches can promote or exacerbate pulmonary hypertension, leading to or worsening right ventricular failure.
A more appealing pharmacological approach might be to inhibit (only) the "correct" NOS isoform, that is, the isoform that is most responsible for promoting deranged cardiovascular function in patients with septic shock. Until fairly recently, most scientists and clinical investigators, who are interested in the pathogenesis and treatment of septic shock, likely would have expressed the view that, among the NOS isoforms, NOS2 is the most appropriate drug target. Certainly, there are data from studies using rodent (22-28) or ovine (29, 30) models of sepsis that lend support to this view. By the same token, however, there are also data in the literature that suggest that selectively inhibiting NOS2 might worsen mortality due to sepsis (31). Could it be that NOSl is a more suitable target? Prompted by idea that excessive production of NO conNOSl was originally identified in rat brain (32, 33), but it tributes to the pathogenesis of circulatory shock, investigators is now recognized that NOSl is found in many different cell have carried out two large, multicentric, placebo-controlled, types, including skeletal muscle cells (34), cardiac myocytes randomized, clinical trials of the isoform nonselective NOS (35, 36), vascular smooth muscle cells (37, 38), and renal macinhibitor, N''-monomethyl-L-arginine ( L - N M M A ) . The first ula densa cells (39). Human NOSl is encoded by a gene located of these trials enrolled patients with septic shock and was on chromosome 12, and several splice variants have been stopped early because of excess mortality among the patients described (40). Some data suggest that a NOSl splice variant randomized to treatment with L - N M M A (17). The second of can be found in mitochondria (41) although the existence and these trials enrolled patients with acute myocardial infarction identity of the putative mitochondrial NOS remains quite concomplicated by cardiogenic shock and was stopped early on troversial (40,42). the basis of a prespecified futility analysis (18). The notion that NOSl might be a key player in the pathophysiology of sepsis probably dates back to work by el-Dwairi Another approach for targeting excessive NO production as a way to ameliorate shock was also evaluated in a large, et al (43), who showed that expression of all three NOS isoforms was up-regulated in skeletal muscle when rats were multicentric, randomized controlled trial. This approach was challenged with LPS. Interest in NOSl as an important gene based on extensive data, showing that hemoglobin effectively product in sepsis and related conditions was enhanced by a scavenges NO (19). In a phase 2 trial, pyridoxalated hemogloseries of articles from Daniel Traber's laboratory in Galveston, bin polyoxyethylene (PHP), a chemically modified cell-free Texas. Eor example, Westphal et al (44) reported that treatment form of human hemoglobin, was shown to ameliorate hypotension and decrease vasopressor requirements in patients with 7-nitroindazole (7-NI), a relatively isoform-selective NOSl antagonist, ameliorated myocardial dysfunction and with distributive (i.e., vasoplegic) shock (20). This preliminary study was followed by a large, multicentric, phase 3 pulmonary edema in sheep subjected to combined burn and smoke inhalation injury. Using the same ovine model, Saunrandomized clinical trial of PHP in patients with distributive shock. The primary endpoint was all-cause mortality at 28 ders et al (45) showed that treatment with 7-NI ameliorated oxidative and nitrosative stress in pulmonary tissue. Lange days after enrollment. The trial was terminated early after the et al (46) employed an ovine model of Pseudomonas aeruginosa third interim analysis of results because the number of deaths pneumonia and showed that treatment with 7-NI ameliorated in the PHP cohort exceeds the number of deaths in the plasystemic arterial hypotension and increased systemic vascular cebo cohort (21). Critical Care Medicine
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Editorials resistance. Treatment with 7-NI was associated with other salutary effects, such as amelioration of hepatocellular injury and metabolic acidosis. Now, in this issue of Critical Care Medicine, Nardi et al (47) have added important information about the role of NOSl in the pathogenesis of circulatory dysfunction in sepsis. These authors studied septic rats. Sepsis was induced by performing a procedure called "CLP" that induces polymicrobial bacterial peritonitis. When the animals were studied 24 hours after the induction of sepsis, treatment with 7-NI or S-methyl-L-thiocitrulline, a potent isoform-selective NOSl inhibitor that is chemically distinct from 7-NI, significantly augmented the pressor response to infusion of norepinephrine. Importantly, the authors showed that sepsis was associated with increased NOSl expression in the wall of the aorta and mesenteric blood vessels. The data obtained by Nardi et al (47) support the view that NOSl may be an attractive drug target as scientists and clinical investigators seek to develop agents to ameliorate circulatory dysfunction in patients with septic shock. Great caution should be exercised in this regard, however, in view of findings that were reported several years ago by Cui et al (48). These investigators subjected wild-type (WT) and NOSl "knockout" (KO) mice (i.e., mice with a genetic deficiency of NOSl) to CLP. Some WT mice were treated with 7-Nl. Sepsis-induced mortality was significantly greater for NOSl KO mice compared with WT mice. Similarly, when septic WT mice were treated with 7-NI, mortality was increased significantly. The mechanism(s) responsible for the deleterious effects of genetic or pharmacological ablation of NOSl-dependent signaling on survival were not elucidated. Nevertheless, circulating levels of certain proinflammatory cytokines were greater in septic NOSl KO mice compared with septic WT mice, suggesting that NOSl-dependent NO production may be important for controlling the inflammatory response to infection. In summary, the true role of NOSl in sepsis remains to be delineated. Some findings suggest that inhibiting this enzyme could be beneficial, whereas other data suggest that this strategy might be deleterious. Additional preclinical studies are clearly warranted.
REFERENCES 1. Garthwaite J, Boulton CL: Nitric oxide signaling in the central nervous system. Annu Rev Physiol 1995; 57:683-706 2. Kroll J, Waltenberger J: VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Bioehem Biophys Res Commun 1998; 252:743-746 3. Bauer V, Sotníková R: Nitric oxide-The endothelium-derived relaxing factor and its role in endothelial functions. Gen Physiol Biophys 2010; 29:319-340 4. Bolotina VM, Najibi S, Palacino JJ, et al: Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1 994; 368:850-853 5. Archer SL, Huang JM, HampI V, et al: Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proe Nati Aead Sei USA 1994; 91:7583-7587 6. Hoque AM, Papapetropoulos A, Venema RC, et al: Effects of antisense oligonucleotide to iNOS on hemodynamic and vascular changes induced by LPS. Am J Physiol 1998; 275:H1078-H1 083
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7 Klein SM, Wong HR, Dayao EK, et al: Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, inos mrna expression and NF-kappaB nuclear translocation in rats. Shock 2000; 14:544-549 8. Wheeler DS, Lahni PM, Hake PW, et al: The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis. Shock 2007; 28:353-359 9. Hollenberg SM, Broussard M, Osman J, et al: Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res 2000; 86:774-778 10. Tsuneyoshi I, Kanmura Y, Yoshimura N: Nitric oxide as a mediator of reduced arterial responsiveness in septic patients. Crit Care Med 1996; 24:1083-1086 11. Avontuur JA, Tutein Nolthenius RP, Buijk SL, et al: Effect of L-NAME, an inhibitor of nitric oxide synthesis, on cardiopulmonary function in human septic shock. Chest 1998; 113:1640-1646 1 2. Kiehl MG, Ostermann H, Meyer J, et al: Nitric oxide synthase inhibition by L-NAME in leukocytopenic patients with severe septic shock. Intensive Care Med 1997; 23:561-566 13. Grover R, Zaccardelli D, Colice G, et al: An open-label dose escalation study of the nitric oxide synthase inhibitor, A/(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo VVellcome International Septic Shock Study Group. Crit Care Med 1999; 27:913-922 14. Stoclet JC, Martinez MC, Ohimann P, et al: Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock. Circulation 1999; 100:107-112 15. Annane D, Sanquer S, Sébille V, et al: Compartmentalised inducible nitric-oxide synthase activity in septic shock. Lancet 2000; 355:1143-1148 16. Reade MC, Millo JL, Young JD, et al: Nitric oxide synthase is downregulated, while haem oxygenase is increased, in patients with septic shock. BrJ Anaesth 2005; 94:468-473 17. López A, Lorente JA, Steingrub J, et al: Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock. Crit Care Med 2004; 32:21-30 18. Alexander JH, Reynolds HR, Stebbins AL, et al; TRIUMPH Investigators: Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: The TRIUMPH randomized controlled trial. JAMA 2007; 297:1657-1666 19. Doherty DH, Doyle MP, Curry SR, et al: Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat Bioteehnol 1998; 16:672-676 20. Kinasewitz GT, Privalle CT, Imm A, et al: Muiticenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock. Crit Care Med 2008; 36:1999-2007 21. Curacyte Health Sciences press release. Munich. Available at: http:// www.curacyte.eu/press_releases.htm. Accessed August, 26, 2011 22. Xie XO, Shinozawa Y, Sasaki J, et al: The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model. J Surg Res 2008; 146:298-303 23. Astolfi RS, Khouri DG, Brandizzi LI, et al: Antagonic effect of the inhibition of inducible nitric oxide on the mortality of mice acutely infected with Escherichia coli and Bacteroides fragilis. Braz J Med Biol Res 2007; 40:317-322 24. Strunk V, Hahnenkamp K, Schneuing M, et al: Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 2001; 92:681-687 25. Wu CC, Chen SJ, Szabó C, et al: Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 1995; 114:1666-1672 26. Lehner MD, Marx D, Boer R, et al: In vivo characterization of the novel imidazopyridine BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]3H-imidazo[4,5-b]pyridine], a potent and highly selective inhibitor of inducible nitric-oxide synthase. J Pharmacol Exp Ther 2006; 317:181-187 June 2014 • Volume 42 • Number 6
Editorials 27 Zheng Y, Lee S, Liang X, et al: Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice. J Infect Dis 2013; 208:1803-1812 28. Aranow JS, Zhuang J, Wang H, et al: A selective inhibitor of inducible in nitric oxide synthase prolongs survival in a rat model of bacterial peritonitis: Comparison with two nonseiective strategies. Shock 1996; 5:116-121 29. Su F, Huang H, Akieda K, et al: Ettects ot a selective iNOS inhibitor versus norepinephrine in the treatment ot septic shock. Shock 2010; 34:243-249 30. Lange M, Hamahata A, Traber DL, et al: Specitie inhibition ot nitric oxide synthases at ditterent time points in a murine model ot pulmonary sepsis. Biochem Biophys Res Commun 2011 ; 404:877-881 31. Cobb JP, Hotehkiss RS, Swanson PE, et al: Indueible nitrie oxide synthase (iNOS) gene detieieney inereases the mortality of sepsis in miee. Surgery 1999; 1 26:438-442 32. Knowles RG, Palaeios M, Palmer RM, et al: Formation of nitrie oxide trom L-arginine in the eentral nervous system: A transduetion mechanism tor stimulation ot the soluble guanylate cyclase. Proc Nati Acad Sei USA1989; 86:5159-5162 33. Bredt DS, Snyder SH: Isolation ot nitric oxide synthetase, a calmodulinrequiring enzyme. Proc Nati Acad Sei USAI 990; 87:682-685 34. Kobzik L, Reid MB, Bredt DS, et al: Nitric oxide in skeletal muscle. Nature 1994; 372:546-548 35. Xu KY, Huso DL, Dawson TM, et al: Nitric oxide synthase in cardiac sareoplasmie retieulum. Proc Nati Acad Sei USA 1999; 96:657-662 36. Ashley EA, Sears CE, Bryant SM, et al: Cardiae nitrie oxide synthase 1 regulates basal and beta-adrenergie contractility in murine ventricular myocytes. Circulation 2002; 1 05:3011 -3016 37. Papadaki M, Tilton RG, Eskin SG, et al: Nitric oxide production by cultured human aortic smooth muscle cells: Stimulation by tluid tlow. Am J Physioi 1998; 274:H61 6-H626 38. Schwarz PM, Kleinert H, Förstermann U: Potential tunctional significance of brain-type and muscle-type nitrie oxide synthase I expressed
in adventitia and media of rat aorta. Arterioscler Thromb Vase Biol 1999; 19:2584-2590 39. Wileox CS, Weleh WJ, Murad F, et al: Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Nati Acad Sei U SA 1992; 89:11993-11997 40. Tengan CH, Rodrigues GS, Godinho RO: Nitrie oxide in skeletal muscle: Role on mitochondrial biogenesis and tunction. Int J Mol Sei 2012; 13:17160-17184 41. Kanai AJ, Pearce LL, Clemens PR, et al: Identitication of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. Proc Nati Acad Sei USA 2001 ; 98:14126-14131 42. Tay YM, Lim KS, Sheu FS, et al: Do mitochondria make nitrie oxide? No? Free Radie Res 2004; 38:591-599 43. el-Dwairi Q, Comtois A, Guo Y, et al: Endotoxin-indueed skeletal muselé eontraetile dysfunetion: Contribution of nitrie oxide synthases. Am J Physiol 1 998; 274:C770-C779 44. Westphal M, Enkhbaatar P, Sehmalstieg FC, et al: Neuronal nitrie oxide synthase inhibition attenuates cardiopulmonary dystunctions after combined burn and smoke inhalation injury in sheep. Crit Care Med 2008; 36:1196-1 204 45. Saunders FD, Westphal M, Enkhbaatar P, et al: Molecular biological effects ot selective neuronal nitrie oxide synthase inhibition in ovine lung injury. Am J Physiol Lung Cell Mol Physioi 2010; 298:L427-L436 46. Lange M, Hamahata A, Traber DL, et al: Etteets ot early neuronal and delayed indueible nitrie oxide synthase bloekade on cardiovascular, renal, and hepatic function in ovine sepsis. Anesthesiology 2010; 113:1376-1384 47 Nardi GM, Scheschowitsch K, Ammar D, et al: Neuronal Nitric Oxide Synthase and Its Interaction With Soluble Guanylyl Cyclase Is a Key Factor tor the Vascular Dystunction of Experimental Sepsis. Crit Care Med 2014; 42:e391-e400 48. Cui X, Besch V, Khaibullina A, et al: Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis. intensive Care Med 2007; 33:1 993-2003
Our Natural Defense: The SkinP Jeremy Goverman, MD, FACS Division of Burns Massachusetts General Hospital Boston, MA
I
n the modern burn ICU, sepsis is attributed to the majority of late deaths after large thermal injury (1-3). Impaired immune function is noted in such patients, the etiology of which is multifactorial, and likely contributes to these deaths (4). Additionally, most of these deaths involve multiple drugresistant microorganisms. The day when Colistin may actually be the appropriate empiric therapy, in at least one burn hospital, is upon us (5); however, traditional antimicrobials 'See also p. e420. Key Words: antimicrobial peptides; barrier tunction; burn; permeability barrier; stratum corneum The author has disclosed that he does not have any potential conflicts ot interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI:10.1097/CCM.0000000000000356
Crifical Care Medicine
will never be a permanent solution to this problem. A more detailed understanding of the host response to burn injury may lead to the development of novel methods of treatment. The skin and its response to injury represent an important area of such research. In this issue of Critical Care Medicine, Plichta et al (6) demonstrate localized and systemic alterations in epithelial barrier function utilizing a murine scald burn model. This work builds on previous research that has shown a number of altered defensive mechanisms present within, and surrounding, burn tissue (7-9). The ability to repair and augment these mechanisms may lead to improvements in burn care. Over the past 10-15 years, researchers have uncovered the complex orchestration of defensive events taking place within our skin, at baseline, and in response to barrier disruption (10-12). The epidermis is a protective, proinflammatory, immune organ, and the majority of its defensive actions take place within the stratum corneum (SC). The SC is made up of two components: cellular (lipid deplete corneocytes) and extracellular (lipid-rich matrix). Each component plays critical and overlapping roles in defending humans from cutaneous microbial invasion. SC defense can be categorized into three areas: 1) a physical barrier; 2) a generator of antimicrobial lipids, peptides, toU-like receptors www.ccmjournal.org
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