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Respiratory Medicine Series Editor: Sharon I.S. Rounds Lynn M. Schnapp Carol Feghali-Bostwick Editors Acute Lung Injury and Repair Scientific Fundamentals and Methods Respiratory Medicine Series editor Sharon I.S. Rounds More information about this series at http://www.springer.com/series/7665 Lynn M. Schnapp Carol Feghali-Bostwick (cid:129) Editors Acute Lung Injury and Repair fi Scienti c Fundamentals and Methods Editors LynnM. Schnapp,MD CarolFeghali-Bostwick, PhD Pulmonary,CriticalCare,AllergyandSleep DivisionofRheumatologyandImmunology Medicine Medical University of SouthCarolina Medical University of SouthCarolina Charleston, SC Charleston, SC USA USA ISSN 2197-7372 ISSN 2197-7380 (electronic) Respiratory Medicine ISBN978-3-319-46525-8 ISBN978-3-319-46527-2 (eBook) DOI 10.1007/978-3-319-46527-2 LibraryofCongressControlNumber:2016951961 ©SpringerInternationalPublishingAG2017 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinor foranyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisHumanaPressimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Contents 1 Methods to Study Lung Injury and Repair: Introduction .... .... 1 Lynn M. Schnapp and Carol Feghali-Bostwick 2 Mouse Models of Acute Lung Injury.... .... .... .... ..... .... 5 William A. Altemeier, Chi F. Hung and Gustavo Matute-Bello 3 Transgenic Animal Models in Lung Research. .... .... ..... .... 25 Chi F. Hung and William A. Altemeier 4 Fundamental Methods for Analysis of Acute Lung Injury in Mice.... ..... .... .... .... .... .... ..... .... 39 Carole L. Wilson, Lindsey M. Felton and Yu-Hua Chow 5 Invasive Measurement of Pulmonary Function in Mice. ..... .... 59 Xiaozhu Huang and Annette Robichaud 6 Analysis of Epithelial Injury and Repair. .... .... .... ..... .... 69 Kathrin Mutze and Melanie Königshoff 7 Flow Cytometric Evaluation of Acute Lung Injury and Repair ... 85 Jason R. Mock, Benjamin D. Singer and Franco R. D’Alessio 8 Lung Imaging in Animal Models... .... .... .... .... ..... .... 107 Emma Lefrançais, Beñat Mallavia and Mark R. Looney 9 Genetic and Genomic Approaches to Acute Lung Injury..... .... 133 Ivana V. Yang 10 MicroRNA Analysis in Acute Lung Injury ... .... .... ..... .... 161 Andrew J. Goodwin Index .... .... .... .... .... ..... .... .... .... .... .... ..... .... 179 v Contributors William A. Altemeier, MD Division of Pulmonary and Critical Care Medicine, Department of Medicine, Center for Lung Biology, University of Washington, Seattle, WA, USA Yu-Hua Chow, PhD Division of Pulmonary and Cricial Care Medicine, University of Washington School of Medicine, Seattle, WA, USA Franco R. D’Alessio, MD Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA Carol Feghali-Bostwick, PhD Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA Lindsey M. Felton, BS Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA AndrewJ.Goodwin,MD,MS DivisionofPulmonary,CriticalCare,Allergyand Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA Xiaozhu Huang, MD Department of Medicine, University of California, San Francisco, CA, USA ChiF.Hung,MD DivisionofPulmonaryandCriticalCareMedicine,Department of Medicine, Center for Lung Biology, University of Washington, Seattle, WA, USA Melanie Königshoff, MD, PhD Comprehensive Pneumology Center (CPC), HelmholtzZentrumMunichandLudwig-Maximilians-UniversityMunich,Munich, Germany Emma Lefrançais, PhD Department of Medicine, University of California, San Francisco, San Francisco, CA, USA Mark R. Looney, MD Department of Medicine, University of California, San Francisco, San Francisco, CA, USA vii viii Contributors Beñat Mallavia, PhD Department of Medicine, University of California, San Francisco, San Francisco, CA, USA Gustavo Matute-Bello, MD Division of Pulmonary and Critical Care Medicine, Department of Medicine, Center for Lung Biology, University of Washington, Seattle, WA, USA Jason R. Mock, MD, PhD Division of Pulmonary Diseases and Critical Care Medicine,UniversityofNorthCarolinaSchoolofMedicine,ChapelHill,NC,USA Kathrin Mutze, PhD Comprehensive Pneumology Center (CPC), Helmholtz Zentrum Munich and Ludwig-Maximilians-University Munich, Munich, Germany Annette Robichaud, PhD SCIREQ Scientific Respiratory Equipment Inc., Montreal, QC, Canada Lynn M. Schnapp, MD Division of Pulmonary,Crticial Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA Benjamin D. Singer, MD Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA CaroleL.Wilson,PhD Division ofPulmonary,CriticalCare,Allergy,andSleep Medicine, Medical University of South Carolina, Charleston, SC, USA Ivana V. Yang, PhD Department of Medicine, University of Colorado Anschutz MedicalCampus,Aurora,USA;DepartmentofEpidemiology,ColoradoSchoolof PublicHealth,Aurora,USA;CenterforGenes,Environment,andHealth,National Jewish Health, Denver, USA Chapter 1 Methods to Study Lung Injury and Repair: Introduction Lynn M. Schnapp and Carol Feghali-Bostwick ARDS Overview The acute respiratory distress syndrome (ARDS), first described in 1967 by Ashbaughandcolleagues[1],continuestohaveupto40 %mortality,representing over 10 % of intensive care unit (ICU) admissions worldwide [2, 3]. Furthermore, theincidenceispredictedtoincreasewiththeagingpopulation[4].Severalclinical disorders can initiate ARDS, including pneumonia, sepsis, gastric aspiration, and trauma. The diagnostic criteria for ARDS have varied over time, which has led to different reports of incidence, morbidity, and mortality. The 2013 “Berlin Definition”wasaconsensusstatementcreatedbyataskforceofARDSexpertsthat builtuponthe1994AECCAmerican-EuropeanConsensusConference’sdefinition statement [5]. The “Berlin Definition” of ARDS includes acute onset (<1 week), bilateralinfiltratesonimaging,hypoxemiadespitepositivepressureventilationand absenceofcongestiveheartfailure(Fig. 1.1).Theclinicalterm“AcuteLungInjury (ALI)” has been replaced by mild, moderate or severe ARDS. This consensus definitionhasimprovedthestandardizationofclinicalresearchandtrials;however, itdoesnottakeintoaccountthecause, orthemechanismofdisease. Developinga molecular classification of the disease is needed to improve diagnosis, prognostication, and treatment. L.M.Schnapp(&) DivisionofPulmonary,CrticialCare,AllergyandSleepMedicine, MedicalUniversityofSouthCarolina,Charleston,SC,USA e-mail:[email protected] C.Feghali-Bostwick DivisionofRheumatology,MedicalUniversityofSouth Carolina,Charleston,SC,USA e-mail:[email protected] ©SpringerInternationalPublishingAG2017 1 L.M.SchnappandC.Feghali-Bostwick(eds.),AcuteLungInjuryandRepair, RespiratoryMedicine,DOI10.1007/978-3-319-46527-2_1 2 L.M.SchnappandC.Feghali-Bostwick Fig.1.1 TypicalARDS chestradiographshowing bilateral,patchyinfiltrates. CourtesyofDr.Andrew Goodwin,MUSC ARDS Pathogenesis ARDS is characterized as an acute diffuse, inflammatory lung injury, leading to increasedpulmonaryvascularpermeability,decreasedlungcompliance,andlossof aerated lung tissue leading to severe perturbations in gas exchange. The classic histologicalfindingofARDSisdiffusealveolardamagewithedema,inflammation, andhyalinemembraneformation[6].Duringtheearly,exudativestage(days1–7), the pathology is dominated by diffuse alveolar damage, epithelial injury and apoptosis,with significantinflammatoryinfiltration,anddisruptionofthecapillary and epithelialbarrierfunctionwithresultant interstitialand intraalveolar edema. In the later fibroproliferative stage, fibroblast proliferation, activation and migration dominate, with type II cell hyperplasia, and fibroproliferation. Interestingly, the majority of patients have resolution of fibroproliferation and pulmonary function improvesovertime.OneoftheunansweredquestionsinARDSiswhatdetermines whether lung injury resolves or progresses to end-stage fibrosis? Why does fibro- proliferation in ARDS resolve, but not in other chronic fibrosing diseases such as Idiopathic Pulmonary Fibrosis? Therapeutic Options The mainstay of treatment of ARDS remains supportive, including avoidance of iatrogenicinjury.TheARDSNetworktrialsdemonstratedimprovedoutcomeswith low tidal volume mechanical ventilation [7], positive end-expiratory pressure [8], and conservative fluid management [9]. However, despite the presence of acute inflammation and role of inflammatory cells such as neutrophils [10], trials tar- geting the inflammatory process have failed to show definitive clinical benefit [2].

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