`ANESTHESIOLOGY
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`The Journal of the American Society of Anesthesiologists, Inc. 0 anesthesiologyorg
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`I
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`‘g‘
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`December 2013
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`Volume 119, Numberé
`ISSN 0003-3022
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`H at: t
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`.m Pioneers in Academic Anesthesiology:
`University of Michigan Medical Center
`Ann Arbor, Michigan
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`Singapore Exhibit 2006
`Singapore Exhibit 2006
`Lassen v. Singapore et al.
`Lassen V. Singapore et a1.
`PGR2019-00053
`‘ PGR2019-00053
`Including 11 Articles and 4 Editorials from or about
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`""
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`Work from the University of Michigan Medical Center
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`ON THE COVER:
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`We continue our end-of-the-year special focus on an institution which has developed and
`maintained research excellence in the specialty. This year a majority of the December issue
`comes from the department of anesthesiology at the University of Michigan (Ann Arbor, Michigan).
`(The heli-photo of the University of Michigan medical center was provided by Dale Fisher.)
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` THIS MONTH IN ANESTHESIOLOGY
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` EDITORIAL VIEWS
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` Translational Research and the Perioperative Phenotype: University of Michigan
` Kevin K. Tremper
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` Increased Risk of Awareness under Anesthesia: An Issue of Consciousness or of Memory?
` Kane O. Pryor and Hugh C. Hemmings, Jr.
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` Complications of Laryngeal Masks in Children: Big Data Comes to Pediatric Anesthesia
` Ronald S. Litman
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` Neural and Immune Consequences of Traumatic Brain Injury: Does Propofol Reduce the
`Impact?
` Robert D. Sanders, Mark Coburn, and Pratik P. Pandharipande
`
` " e Scientifi c Journey to Predicting and Preventing Postoperative Pain: Recalling Dr. Wall’s Stories
`along the Way
` Samuel A. McLean
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` “Seeing” How Our Drugs Work Brings Translational Added Value
` Irene Tracey
`
` Equivalent Effi cacy of Hydroxyethyl Starch 130/0.4 and Human Serum Albumin: If Nothing Is the
`Same, Is Everything Diff erent? " e Importance of Context in Clinical Trials and Statistics
` Richard B. Weiskopf
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` SPECIAL ARTICLES
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` Altered States: Psychedelics and Anesthetics
` Eduardo E. Icaza and George A. Mashour
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`1A
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`1233
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`1241
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`◇ Refers to This Month in Anesthesiology
`◆ Refers to Editorial Views
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` This article is from or about the
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`University of Michigan
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`c See Supplemental Digital Content
` CME Article
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`Downloaded from anesthesiology.pubs.asahq.org by guest on 10/29/2019
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`CONTENTS
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`
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`
`
` An Analysis of Methodologies " at Can Be Used to Validate if a Perioperative Surgical
`Home Improves the Patient-centeredness, Evidence-based Practice, Quality, Safety, and Value
`of Patient Care
`1261
` Thomas R. Vetter, Nataliya V. Ivankova, Lee A. Goeddel, Gerald McGwin, Jr., and
`Jean-Francois Pittet for the UAB Perioperative Surgical Home Group
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` PERIOPERATIVE MEDICINE
`
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`◇ ◆
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` Increased Risk of Intraoperative Awareness in Patients with a History of Awareness
` Amrita Aranake, Stephen Gradwohl, Arbi Ben-Abdallah, Nan Lin, Amy Shanks,
`Daniel L. Helsten, David B. Glick, Eric Jacobsohn, Alex J. Villafranca, Alex S. Evers,
`Michael S. Avidan, and George A. Mashour
`
`1275
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` In a matched cohort analysis of patients drawn from three trials including over 25,000 patients, those with a history of
`intraoperative awareness had a fi ve-fold increased incidence of awareness compared with propensity-matched controls who
`did not have a history of awareness. Anesthetic management did not diff er between the cohorts; in view of the likely increased
`risk of awareness, clinicians should consider modifying anesthetic management in patients with a history of awareness.
`
` ◆
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` Failure of the Laryngeal Mask Airway Unique™ and Classic™ in the Pediatric Surgical Patient:
`A Study of Clinical Predictors and Outcomes
`1284
` Michael R. Mathis, Bishr Haydar, Emma L. Taylor, Michelle Morris, Shobha V. Malviya,
`Robert E. Christensen, Satya-Krishna Ramachandran, and Sachin Kheterpal
`
` # is study evidenced that laryngeal mask airway failures occur in 0.86% of 11,910 pediatric anesthesia cases with its
`planned use, and are independently associated with ear/nose/throat procedures, admission status, prolonged surgical
`duration, airway abnormalities, and patient transport.
`
` ◆ Six Percent Hydroxyethyl Starch 130/0.4 (Voluven®) versus 5% Human Serum Albumin
`for Volume Replacement " erapy during Elective Open-heart Surgery in Pediatric Patients 1296
` Philippe Van der Linden, Andrée De Villé, Anna Hofer, Martina Heschl, and Hans Gombotz
`
` # is randomized clinical trial demonstrated equivalent effi cacy of human albumin versus hydroxyethyl starch for volume
`replacement in 61 children undergoing cardiac surgery. Although the trial was not powered to assess safety, outcomes
`measures were not diff erent between the groups.
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` Patient Selection for Day Case-eligible Surgery: Identifying " ose at High Risk for
`Major Complications
` Michael R. Mathis, Norah N. Naughton, Amy M. Shanks, Robert E. Freundlich,
`Christopher J. Pannucci, YiJia Chu, Jason Haus, Michelle Morris, and Sachin Kheterpal
`
`1310
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` In a review of nearly 250,000 cases in the National Surgery Quality Improvement Program, early perioperative
`morbidity and mortality occurred in approximately 1:1,000 patients. Predictors for morbidity and mortality were
`overweight or obesity, chronic obstructive pulmonary disease, history of transient ischemic attack/stroke, hypertension,
`prior cardiac surgical intervention, and prolonged operative time.
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` ◇
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` Predictors of Survival from Perioperative Cardiopulmonary Arrests: A Retrospective Analysis
`of 2,524 Events from the Get With " e Guidelines-Resuscitation Registry
`1322
` Satya Krishna Ramachandran, Jill Mhyre, Sachin Kheterpal, Robert E. Christensen,
`Kristen Tallman, Michelle Morris, and Paul S. Chan, for the American
`Heart Association’s Get With The Guidelines-Resuscitation Investigators
`
` One third of patients with perioperative cardiac arrests survive to hospital discharge. Two thirds of survivors have good
`neurological outcome. Shockable rhythms and asystolic arrests were associated with signifi cant location-specifi c survival variance.
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` Perioperative Metoprolol and Risk of Stroke after Noncardiac Surgery
` George A. Mashour, Milad Sharifpour, Robert E. Freundlich, Kevin K. Tremper, Amy Shanks,
`Brahmajee K. Nallamothu, Phillip E. Vlisides, Adam Weightman, Lisa Matlen, Janna Merte,
`and Sachin Kheterpal
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`1340
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` In this retrospective study, routine use of preoperative and intraoperative metoprolol—but not other β blockers—was
`associated with increased risk of stroke after noncardiac surgery. # ese data suggest that results of the POISE trial may
`have refl ected a drug-specifi c eff ect of metoprolol in perioperative stroke.
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`CONTENTS
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` Reconfi guration of Network Hub Structure after Propofol-induced Unconsciousness
` Heonsoo Lee, George A. Mashour, Gyu-Jeong Noh, Seunghwan Kim, and UnCheol Lee
`
`1347
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` Propofol reconfi gures the brain’s network hub structure. Reconfi guration of hub structure may explain the observed loss
`of frontal–parietal feedback connectivity.
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` Incidence, Predictors, and Outcome of Diffi cult Mask Ventilation Combined with
`Diffi cult Laryngoscopy: A Report from the Multicenter Perioperative Outcomes Group
` Sachin Kheterpal, David Healy, Michael F. Aziz, Amy M. Shanks, Robert E. Freundlich,
`Fiona Linton, Lizabeth D. Martin, Jonathan Linton, Jerry L. Epps, Ana Fernandez-Bustamante,
`Leslie C. Jameson, Tyler Tremper, and Kevin K. Tremper, on behalf of the Multicenter
`Perioperative Outcomes Group (MPOG) Perioperative Clinical Research Committee
`
`1360
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` # is study determined incidence of diffi cult mask ventilation combined with diffi cult laryngoscopy to be 0.4% of
`176,679 adult cases, and succeeded in identifying 12 independent predictors for the critical situation.
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` CRITICAL CARE MEDICINE
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` ◆ Propofol Limits Microglial Activation after Experimental Brain Trauma through Inhibition
`of Nicotinamide Adenine Dinucleotide Phosphate Oxidase
` Tao Luo, Junfang Wu, Shruti V. Kabadi, Boris Sabirzhanov, Kelsey Guanciale, Marie Hanscom,
`Juliane Faden, Katherine Cardiff, Charles Jeremy Bengson, and Alan I. Faden
`
`1370
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` Propofol reduces functional defi cit after traumatic brain injury, in an animal model. # ese neuroprotective eff ects are
`mediated in part by inhibition of microglial nicotinamide adenine dinucleotide phosphate oxidase.
`
`
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` Critical Role of Interleukin-11 in Isofl urane-mediated Protection against Ischemic Acute
`Kidney Injury in Mice
` Ahrom Ham, Mihwa Kim, Joo Yun Kim, Kevin M. Brown, James Yeh, Vivette D. D’Agati, and
`H. Thomas Lee
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` Isofl urane increased interleukin-11 synthesis in human and mouse proximal tubular cells via TGF-β1 signaling to
`protect against ischemic acute kidney injury.
`
` c Positive End-expiratory Pressure Increments during Anesthesia in Normal Lung Result
`in Hysteresis and Greater Numbers of Smaller Aerated Airspaces
` Maurizio Cereda, Yi Xin, Kiarash Emami, Jessie Huang, Jennia Rajaei, Harrilla Profka,
`Biao Han, Puttisarn Mongkolwisetwara, Stephen Kadlecek, Nicholas N. Kuzma,
`Stephen Pickup, Brian P. Kavanagh, Clifford S. Deutschman, and Rahim R. Rizi
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` In healthy rats, larger lung volumes due to hysteresis were associated with smaller individual airspace dimensions,
`suggesting opening of previously nonaerated peripheral airspaces, rather than expansion of already opened airspaces.
`SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT
`
`1389
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`1402
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` PAIN MEDICINE
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` ◆ c Pain in 1,000 Women Treated for Breast Cancer: A Prospective Study of Pain Sensitivity
`and Postoperative Pain
` Mari A. Kaunisto, Ritva Jokela, Minna Tallgren, Oleg Kambur, Emmi Tikkanen, Tiina Tasmuth,
`Reetta Sipilä, Aarno Palotie, Ann-Mari Estlander, Marjut Leidenius, Samuli Ripatti, and Eija A. Kalso
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`1410
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` In a study of 1,000 women undergoing breast surgery for cancer, a small portion of the variance in preoperative response
`to noxious heat and cold testing could be explained by anxiety, the presence of chronic pain, and the number of previous
`operations. # ere was a weak correlation between response to experimental pain testing and acute postoperative pain, with
`largely similar predictive factors across both. SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT
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`CONTENTS
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` ◇ ◆ c Eff ect of Catechol-o-methyltransferase-gene (COMT ) Variants on Experimental and
`Acute Postoperative Pain in 1,000 Women undergoing Surgery for Breast Cancer
` Oleg Kambur, Mari A. Kaunisto, Emmi Tikkanen, Suzanne M. Leal, Samuli Ripatti, and
`Eija A. Kalso
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` In a more complete assessment of variants in the COMT gene in 1,000 women undergoing surgery for breast cancer,
`there were weak associations with sensitivity to heat or cold pain. # e lack of association of COMT variants with acute
`postoperative opioid requirement raises questions regarding the clinical relevance of this gene in acute postoperative pain.
`SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT
`
` c
`
` Survey Criteria for Fibromyalgia Independently Predict Increased Postoperative Opioid
`Consumption after Lower-extremity Joint Arthroplasty: A Prospective, Observational
`Cohort Study
` Chad M. Brummett, Allison M. Janda, Christa M. Schueller, Alex Tsodikov, Michelle Morris,
`David A. Williams, and Daniel J. Clauw
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` Even though less than 9% of participants met “criteria” for fi bromyalgia, increasing degrees of fi bromyalgia-like
`symptoms were independently predictive of increased postoperative opioid requirements. SUPPLEMENTAL DIGITAL
`CONTENT IS AVAILABLE IN THE TEXT
`
` c Lidocaine Patch (5%) in Treatment of Persistent Inguinal Postherniorrhaphy Pain: A
`Randomized, Double-blind, Placebo-controlled, Crossover Trial
` Joakim M. Bischoff, Marian Petersen, Nurcan Üçeyler, Claudia Sommer, Henrik Kehlet, and
`Mads U. Werner
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` Lidocaine patches (5%) caused pressure pain threshold increases when compared with placebo patch treatment.
`However, lidocaine patch treatment did not lead to decreases in summed pain intensity diff erences. SUPPLEMENTAL
`DIGITAL CONTENT IS AVAILABLE IN THE TEXT
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` ◆
`
` Pregabalin Rectifi es Aberrant Brain Chemistry, Connectivity, and Functional Response
`in Chronic Pain Patients
` Richard E. Harris, Vitaly Napadow, John P. Huggins, Lynne Pauer, Jieun Kim,
`Johnson Hampson, Pia C. Sundgren, Bradley Foerster, Myria Petrou, Tobias Schmidt-Wilcke,
`and Daniel J. Clauw
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` Using three complementary imaging techniques (proton magnetic resonance spectroscopy, functional magnetic
`resonance imaging, and functional connectivity) in chronic pain patients with fi bromyalgia, it was shown that
`pregabalin treatment reduced brain insula glutamate levels and was associated with decreased connectivity of this
`structure to the default mode network.
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` CLASSIC PAPERS REVISITED
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` " erapeutic Benefi t of the Anesthesiologist–Patient Relationship
` Lawrence D. Egbert and Stephen H. Jackson
`
` # is article is a revisiting of original material published as: Egbert LD, Battit GE, Turndorf H, Beecher HK: # e value
`of the preoperative visit by an anesthetist: A study of doctor–patient rapport. JAMA 1963; 185:553–5.
`
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` EDUCATION
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` IMAGES IN ANESTHESIOLOGY
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` Icteric Vocal Cords Recorded during Video Laryngoscopy
` Richard M. Cooper
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` Anomalous Origin of the Left Pulmonary Artery from the Right Pulmonary Artery
`(Pulmonary Artery Sling)
` Ahmad Zabad and Mohanad Shukry
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`1422
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`CONTENTS
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`ANESTHESIA LITERATURE REVIEW
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`REVIEW ARTICLE
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` Perioperative Organ Injury
`Karsten Bartels, Jörn Karhausen, Eric T. Clambey, Almut Grenz, and Holger K. Eltzschig
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`Prevention and treatment of acute organ injury in surgical patients represents a critical challenge for the field of
`perioperative medicine. Here, the authors discuss manifestations of perioperative organ injury and provide examples for
`novel treatment approaches.
`
`MIND TO MIND
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` Value-based Healthcare
`Yuriy S. Bronshteyn
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` I Am With You
`George Williams
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` A Critical Care Holiday Poem
`Lance M. Retherford
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` ANESTHESIOLOGY REFLECTIONS FROM
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`THE WOOD LIBRARY-MUSEUM
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` “I Awaken to Glory”
`George S. Bause
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` Man and His Health
`George S. Bause
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` Colon-Morales’ Uterine Displacement Device
`George S. Bause
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` REVIEWS OF EDUCATIONAL MATERIAL
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` CAREERS & EVENTS
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`1471
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`1474
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`1490
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`1492
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`1493
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`1246
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`17A
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`CONTENTS
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`INSTRUCTIONS FOR AUTHORS
`
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`Critical Role of Interleukin-11 in Isoflurane-mediated
`Protection against Ischemic Acute Kidney Injury in Mice
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`(cid:34)(cid:73)(cid:83)(cid:80)(cid:78)(cid:1)(cid:41)(cid:66)(cid:78)(cid:13)(cid:1)(cid:49)(cid:73)(cid:15)(cid:37)(cid:15)(cid:13)(cid:11)(cid:1)(cid:46)(cid:74)(cid:73)(cid:88)(cid:66)(cid:1)(cid:44)(cid:74)(cid:78)(cid:13)(cid:1)(cid:49)(cid:73)(cid:66)(cid:83)(cid:78)(cid:15)(cid:37)(cid:15)(cid:13)(cid:112)(cid:1)(cid:43)(cid:80)(cid:80)(cid:1)(cid:58)(cid:86)(cid:79)(cid:1)(cid:44)(cid:74)(cid:78)(cid:13)(cid:1)(cid:49)(cid:73)(cid:15)(cid:37)(cid:15)(cid:13)(cid:11)(cid:1)(cid:44)(cid:70)(cid:87)(cid:74)(cid:79)(cid:1)(cid:46)(cid:15)(cid:1)(cid:35)(cid:83)(cid:80)(cid:88)(cid:79)(cid:13)(cid:1)(cid:35)(cid:15)(cid:52)(cid:15)(cid:13)(cid:112)(cid:1)(cid:1)
`(cid:43)(cid:66)(cid:78)(cid:70)(cid:84)(cid:1)(cid:58)(cid:70)(cid:73)(cid:13)(cid:1)(cid:35)(cid:15)(cid:52)(cid:15)(cid:13)(cid:113)(cid:1)(cid:55)(cid:74)(cid:87)(cid:70)(cid:85)(cid:85)(cid:70)(cid:1)(cid:37)(cid:15)(cid:1)(cid:37)(cid:8)(cid:34)(cid:72)(cid:66)(cid:85)(cid:74)(cid:13)(cid:1)(cid:46)(cid:15)(cid:37)(cid:15)(cid:13)(cid:102)(cid:1)(cid:41)(cid:15)(cid:1)(cid:53)(cid:73)(cid:80)(cid:78)(cid:66)(cid:84)(cid:1)(cid:45)(cid:70)(cid:70)(cid:13)(cid:1)(cid:46)(cid:15)(cid:37)(cid:15)║
`
`ABSTRACT
`
`Background: Isoflurane releases renal tubular transforming
`growth factor-β1 (TGF-β1) and protects against ischemic
`acute kidney injury. Recent studies suggest that TGF-β1 can
`induce a cytoprotective cytokine interleukin (IL)-11. In this
`study, the authors tested the hypothesis that isoflurane pro-
`tects against ischemic acute kidney injury by direct induc-
`tion of renal tubular IL-11 synthesis.
`Methods: Human kidney proximal tubule cells were treated
`with 1.25–2.5% isoflurane or carrier gas (room air + 5%
`carbon dioxide) for 0–16 h. "e authors also anesthetized
`C57BL/6 mice with 1.2% isoflurane or with equianesthetic
`dose of pentobarbital for 4 h. In addition, the authors sub-
`jected IL-11 receptor (IL-11R) wild-type, IL-11R–deficient,
`or IL-11 neutralized mice to 30-min renal ischemia followed
`by reperfusion under 4 h of anesthesia with pentobarbital or
`isoflurane (1.2%).
`Results: Isoflurane increased IL-11 synthesis in human
`(approximately 300–500% increase, N = 6) and mouse
`(23 ± 4 [mean ± SD] fold over carrier gas group, N = 4)
`proximal tubule cells that were attenuated by a TGF-β1–
`neutralizing antibody. Mice anesthetized with isoflurane
`showed significantly increased kidney IL-11 messenger
`RNA (13.8 ± 2 fold over carrier gas group, N = 4) and pro-
`tein (31 ± 9 vs. 18 ± 2 pg/mg protein or approximately 80%
`increase, N = 4) expression compared with pentobarbital-
`anesthetized mice, and this increase was also attenuated by
`
`* Postdoctoral Research Scientist, † Research Associate, ‡ Research
`Student, ║ Professor, Department of Anesthesiology, §  Professor,
`Department of Pathology, College of Physicians and Surgeons of
`Columbia University, New York, New York.
`
`Received from the Department of Anesthesiology, Columbia
`University, New York, New York. Submitted for publication April
`30, 2013. Accepted for publication August 8, 2013. This work was
`supported in part by the Department of Anesthesiology, Colum-
`bia University, New York, New York, and R01 DK-058547 and R01
`GM-067081 (to Dr. Lee) from the National Institutes of Health,
`Bethesda, Maryland. The authors declare no competing interests.
`
`Address correspondence to Dr. Lee: Department of Anesthe-
`siology, Anesthesiology Research Laboratories, Columbia Univer-
`sity, P&S Box  46 (PH-5), 630 West 168th Street, New York, New
`York 10032–3784. tl128@columbia.edu. Information on purchasing
`reprints may be found at www.anesthesiology.org or on the mast-
`head page at the beginning of this issue. ANESTHESIOLOGY’S articles
`are made freely accessible to all readers, for personal use only, 6
`months from the cover date of the issue.
`
`Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott
`Williams & Wilkins. Anesthesiology 2013; 119:1389-401
`
`What We Already Know about This Topic
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`
`What This Article Tells Us That Is New
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`
`a TGF-β1–neutralizing antibody. Furthermore, isoflurane-
`mediated renal protection in IL-11R wild-type mice was
`absent in IL-11R–deficient mice or in IL-11R wild-type
`mice treated with IL-11–neutralizing antibody (N = 4–6).
`Conclusion: In this study, the authors suggest that isoflu-
`rane induces renal tubular IL-11 via TGF-β1 signaling to
`protect against ischemic acute kidney injury.
`
`ACUTE kidney injury (AKI) remains a major periopera-
`
`tive complication and results in extremely high mortal-
`ity and morbidity costing more than 10 billion dollars per
`year in the United States.1,2 Furthermore, AKI is frequently
`associated with other life-threatening complications includ-
`ing remote multiorgan injury and sepsis.2–5 Renal ischemia–
`reperfusion (I/R) injury or ischemic AKI is a frequent
`complication for patients subjected to major cardiac, hepa-
`tobiliary, or transplant surgery.3,6 Unfortunately, there is no
`effective clinically proven therapy for ischemic AKI. Further-
`more, patients who survive initial renal injury frequently suf-
`fer from long-term chronic kidney disease.
`Volatile halogenated anesthetics are one of the most widely
`used drugs during the perioperative period.7 Our previous
`studies demonstrated that clinically used volatile halogenated
`anesthetics including isoflurane at clinically relevant con-
`centrations (approximately 1–2 minimum alveolar concen-
`tration) protect against ischemic AKI by attenuating renal
`tubular necrosis and by retarding renal tubular inflammation
`with reduction in influx of proinflammatory leukocytes.8,9
`We also demonstrated that volatile halogenated anesthetics
`produce direct antiinflammatory and antinecrotic effects in
`cultured human kidney proximal tubule (HK-2) cells.10,11
`Subsequently, we discovered that volatile halogenated anes-
`thetics protect against renal tubular necrosis and inflammation
`by direct renal tubular production of transforming growth
`factor-β1 (TGF-β1).11–13 However, the downstream signaling
`
`(cid:34)(cid:79)(cid:70)(cid:84)(cid:85)(cid:73)(cid:70)(cid:84)(cid:74)(cid:80)(cid:77)(cid:80)(cid:72)(cid:90)(cid:13)(cid:1)(cid:55)(cid:1)(cid:18)(cid:18)(cid:26)(cid:1)(cid:116)(cid:1)(cid:47)(cid:80)(cid:1)(cid:23)
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`

`mechanisms of volatile halogenated anesthetic-mediated renal
`protection generated by TGF-β1 remain incompletely under-
`stood. Moreover, isoflurane therapy for critically ill patients
`may be limited by its anesthetic and cardiovascular effects.
`One way to mitigate this is to use the distal signaling mole-
`cules synthesized with isoflurane treatment devoid of systemic
`hemodynamic and anesthetic effects.
`Interleukin (IL)-11 is a 20 kDa member of the IL-6-type
`cytokine family. IL-11 promotes megakaryocyte maturation
`and is already clinically approved to increase platelet counts
`in patients receiving chemotherapy.14 In addition to its hema-
`topoietic effects, IL-11 protects against intestinal, cardiomyo-
`cyte, and endothelial cell death.15 We recently showed that
`recombinant human IL-11 treatment before or after renal
`ischemia attenuated ischemic AKI in mice.16 Specifically,
`IL-11 administration significantly attenuated necrosis, inflam-
`mation, and apoptosis after ischemic AKI closely mimicking
`the renal protective effects of volatile halogenated anesthetics.
`"is IL-11–mediated protection against ischemic AKI requires
`the downstream induction of another cytoprotective protein
`sphingosine kinase-1. Interestingly, we also showed that isoflu-
`rane-mediated protection against ischemic AKI also requires
`induction of sphingosine kinase-1.17 Finally, previous studies
`suggest that TGF-β1 induces IL-11 in lung epithelial cells and
`fibroblasts.18,19 "erefore, in this study, we tested the hypoth-
`esis that isoflurane induces TGF-β1–mediated renal proximal
`tubular IL-11 synthesis. We also tested whether IL-11 plays a
`critical role in isoflurane-mediated renal protection.
`
`Materials and Methods
`
`Human and Mouse Proximal Tubule Cell Culture and
`Exposure to Isoflurane
`Immortalized human renal proximal tubule (HK-2) cells
`(American Type Culture Collection, Manassas, VA) were
`grown and passaged with 50:50 mixture of Dulbecco Modi-
`fied Eagle Media/F12 with 10% fetal bovine serum (Invitro-
`gen, Carlsbad, CA) and antibiotics (100 U/ml penicillin G,
`100 µg/ml streptomycin, and 0.25 µg/ml amphotericin B;
`Invitrogen) at 37°C in a 100% humidified atmosphere of 5%
`carbon dioxide–95% air. "is cell line has been characterized
`extensively and retains the phenotypic and functional charac-
`teristics of proximal tubule cells in culture.20 We also cultured
`mouse kidney proximal tubule cells. Mouse kidneys were
`removed, minced, and digested in collagenase A (1 mg/ml;
`Sigma, St. Louis, MO) at 37°C for 45 min with occasional agi-
`tation. "e cellular digest was filtered through a nylon mesh,
`centrifuged at 600g for 10 min, and washed twice. Mouse kid-
`ney proximal tubules were isolated according to the method
`by Vinay et al.21 with the use of Percoll density gradient sepa-
`ration. Cells were used in the experiments described below
`when confluent after 24-h serum deprivation.
`HK-2 cells or mouse proximal tubules in culture were
`placed in an air tight, 37°C, humidified modular incuba-
`