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An Official American Thoracic Society Workshop Report: ComparativePathobiology of Fibrosing Lung Disorders in Humansand Domestic AnimalsJesse Roman, Kevin K. Brown, Amy Olson, Brendan M. Corcoran, and Kurt J. Williams; on behalf of the ATSComparative Biology of Lung Fibrosis Working Group

THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, MAY 2013

Abstract

Background: The clinical outcome of idiopathic pulmonaryfibrosis (IPF) is poor, with a 50% survival rate at 3 years. Furthermore,current treatments provide little amelioration of symptoms. Despitesignificant advances in understanding the clinical features andpathobiology of IPF, further advances have been hampered by a lackof suitable animalmodels of the disease. Interestingly, spontaneouslyoccurring disorders with a similarity to IPF have been recognized inthe dog, cat, horse, and donkey. These disorders share clinical andpathologic features with human IPF and are emerging diseases ofveterinary importance.

Purpose: To improve awareness about these disorders in domesticanimals and stimulate interactions between disciplines, and tofacilitate the elucidation of mechanisms of fibrosing lung disordersusing a comparative natural-occurrence disease model approach.

Methods: A 1-day meeting joined physicians, veterinarians,pathologists, researchers, and advocacy experts to discussinformation available in this area. A review of the literature wasconducted, and an executive committee discussed the findings andprepared a summary statement during subsequent meetings.

Results: Clinical, diagnostic, and treatment opportunities wereidentified, and common areas of interest where collaborative effortscould accelerate discovery regarding etiological factors, methods forearly detection, determinants of disease progression, and noveltherapies were defined.

Conclusions: Comparing fibrosing lung disorders in humans anddomestic animals will allow for a better understanding of thesimilarities and differences among species and may offer novelinsights into the underlyingmechanisms of spontaneously occurringfibrotic lung diseases.

Keywords: lung fibrosis; comparative biology; domestic animals

Supported by the Westie Foundation of America and the American Thoracic Society.

Ann Am Thorac Soc Vol 10, No 6, pp S224–S229, Dec 2013Copyright © 2013 by the American Thoracic SocietyDOI: 10.1513/AnnalsATS.201309-321STInternet address: www.atsjournals.org

CONTENTS

Executive SummaryIntroductionMethodsWorkshop DiscussionResearch RecommendationsSummary

Executive Summary

Idiopathic pulmonary fibrosis (IPF)continues to be an enigmatic disorder withpoor outcomes and limited treatment

options. Interestingly, pulmonary disorderswith similar clinical features are increasinglyidentified in animals such as dogs, cats,and horses, among others. Because they arelong lived and share the same environmentwith humans, these animals mightrepresent models of spontaneouslyoccurring, progressive lung fibrosis.Learning about the pathogenesis of theseconditions may provide novel insights thatcould be translated to the human conditionand lead to the development of effectivetherapies in both humans and animals. Toidentify common areas of interest wherecollaborative efforts could accelerate

discovery about the etiology of thesedisorders, the factors that influence diseaseprogression, and the development ofeffective therapies, a 1-day meetingsponsored by the Westie Foundation ofAmerica joined physicians, veterinarians,pathologists, researchers, and advocacyexperts to discuss the information availablein this area. Subsequently, a Working Groupon Comparative Biology of Lung Fibrosiswas established by the Respiratory Cell andMolecular Biology (RCMB) Assembly ofthe American Thoracic Society. Togetherwith information gathered at the meeting,a review of the literature, and discussions

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held through meetings and telephoneconversations, the group came to thefollowing conclusions:

d Although fibrotic lung disorders havebeen described for many years in horses,they have only more recently beendescribed in other species, and there islittle awareness of their occurrence in boththe medical and veterinary communities.

d Significant advances have been made inthe understanding of the clinicalpresentation, diagnostic methods, andtreatment options in IPF; however, theseadvances have not led to safe and effectivetherapies capable of improving survivalin this condition. Even less is knownregarding pulmonary fibrosis in animals.

d Difficulties inherent in obtaining reliableinformation regarding the clinicalpresentation, physiology, imaging patternsof disease, and histopathology havegreatly hampered progress in this area.

Considering the above, and to improveawareness and accelerate discovery thatcould lead to important advancements inthis area, the group made the followingresearch recommendations:

d Detailed descriptive studies should beconducted in affected domestic animalsto define the clinical, imaging, andpathological presentation of pulmonaryfibrosis in these species.

d Genetic studies and other pathogenesis-based investigations should be conductedin naturally occurring spontaneousmodels of pulmonary fibrosis toinvestigate the potential translation toIPF in humans. These models shouldprovide more relevant tools to investigatethe potential effectiveness of novelantifibrosis drugs in prehuman trials.

d Studies should be conducted to define theanatomical and cellular differences in thelungs of different species for the adequateinterpretation of discordant findings.

d Suitable reagents needed to adequatelytest hypotheses in different species ofanimals should be generated.

d A consortium of interested centers anda central repository of clinicalinformation and biologic specimens fromnaturally occurring spontaneous modelsof lung fibrosis in domestic animalsshould be established to enable furtherresearch that may benefit both physiciansand veterinarians in their efforts to

adequately manage lung fibrosis in theirpatient populations.

d Another workshop including physicianand veterinary experts, pathologists,community advocates, and representativesof private foundations, industry andbiotechnology, and federal scientificorganizations should be conducted to definespecific hypotheses to be tested acrossspecies and the approaches to be used.

Introduction

Idiopathic pulmonary fibrosis (IPF) isa pulmonary disorder characterized byprogressive deposition of interstitialcollagens and other extracellular matrixcomponents in the lung, leading to fibrosisthat invariably culminates in respiratoryfailure and death despite current therapeuticinterventions, save for lung transplantation(1). The incidence of IPF is increasing inindustrial nations, currently affecting morethan 150,000 people in the United Statesalone, and more than 5,000 new cases arebeing identified annually in the UnitedKingdom, with many hundreds ofthousands afflicted worldwide. Biomedicalresearch into the molecular and geneticmechanisms of lung fibrosis has expandedour understanding of the processes that canlead to pulmonary fibrosis, but this workhas not led to appreciable increases in thelife expectancy of patients with IPF. Indeed,despite the considerable investment madeto date, there are no Federal DrugAdministration–approved drugs proven toprolong survival in patients with IPF (2, 3).

Central to the failure to makesignificant progress in understanding thepathogenesis of IPF and, by extension, todevelop effective therapies and improve theclinical outcome in people with IPF, is thelack of an animal model that shares theprogressive clinical course and pathologicfeatures of the disease. The importance ofthis deficiency was highlighted in a 2002summary of “Future Research Directions inIPF” released by a National Heart, Lung,and Blood Institute Working Group (4).More recently, Hunninghake and Schwarzsuggested that data generated in vitro or inanimal (i.e., rodent) models of lung fibrosisshould not necessarily be assumed totranslate to human IPF unless and untiltherapeutic intervention directed againstsuch pathways or molecules is shown toameliorate the clinical progression of the

disease or alter the histologic lungremodeling characteristic of IPF (5).

Unbeknownst to much of the medicalcommunity, spontaneous progressivefibrosing lung diseases are not restricted tohuman medicine; such diseases have beenrecognized for more than a decade inveterinary medicine in a variety of domesticanimal species—most notably cats, dogs,and horses (6, 7). These disorders havereceived little attention in the biomedicalcommunity outside of veterinary medicine.Given that the affected species are long-livedanimals that share a common environmentwith humans, they might represent potentialmodels of spontaneously occurring, progressivelung fibrosis. Thus, it is conceivable thatinvestigating fibrosing lung disease in thesespecies could accelerate the development ofeffective strategies for the prevention andtreatment of fibrosing lung disorders in bothhumans and domestic animals.

Methods

To improve awareness and communicationregarding spontaneous progressive fibroticlung disorders in mammals and to stimulateinteraction between human and veterinarymedical professionals, the Westie Foundationof America (WFA) sponsored a 1-daymeetingin October 2007 held in Lafayette, Indiana.The Westie Foundation of America, Inc. isa nonprofit corporation, recognized by theIRS as a 501 (C) (3) organization. Its missionis to provide financial aid and other supportfor medical research in order to benefit thehealth and quality of life of West HighlandWhite Terriers; and to further develop andcommunicate information regarding thehealth, care, breeding, and quality of life ofWesties to Westie owners, Westie breeders,and veterinarians. The aim of the WFA inorganizing this symposium was to bringtogether a focused group of internationalphysicians, veterinarians, pathologists,researchers, and advocacy experts to discussfibrotic lung disorders in humans anddomestic animals (see list of participants atthe end of this article).

Leadership of the WFA, incommunication with experts in the field,selected the participants for the symposium.Subsequently, a working group from thismeeting was established by the AmericanThoracic Society’s (ATS) RespiratoryCell and Molecular Biology (RCMB)Assembly. Members of this working group

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were selected from participants of thesymposium, as well as members of theRCMB Lung Fibrosis Working Groupinterested in this topic, and were vetted forpotential conflicts of interest according tothe policies and procedures of the ATS.

This group met in May 2009 and 2010in conjunction with the International ATSConferences held in San Diego, Californiaand New Orleans, Louisiana, respectively.The objectives of this working group were toextend the work performed at the Indianameeting to identify new clinical, diagnostic,and treatment opportunities in IPF andrelated fibrotic lung disorders; to definecommon areas of interest where collaborativeefforts could help accelerate the discovery ofetiological factors, methods for early detection,determinants of disease progression, and noveltherapies; and to generate recommendationsthat could serve to guide investigators andcommunity advocates regarding investments infuture research. Literature searches wereconducted by several group members usingboth traditional biomedical and veterinarymedicine search engines. Finally, a writingcommittee was established among themembers of the working group andparticipants of the symposium to makeresearch recommendations. Recommendationswere formulated and differences were resolvedby discussion and consensus (see Table 1).

Workshop Discussion

At the October 2007 meeting, physicianexperts in the area of IPF discussed thecurrent state of knowledge regarding theidiopathic interstitial pneumonias (IIP) anddescribed their clinical presentation,histology, and radiographic findings, usingIPF as a prototype of IIP. In addition,researchers discussed processes related toepithelial cell injury, fibroblast differentiationand proliferation, matrix remodeling,surfactant protein mutations, viruses, andother potential etiologic factors andmechanisms implicated in the pathogenesisof IPF. Critical gaps in knowledge werediscussed and the state of clinical trials wasaddressed. Further information about IPFcan be found in recently published clinicalpractice guidelines from the AmericanThoracic Society, European RespiratorySociety, Latin American Thoracic Society,and Japanese Respiratory Society (8).

Veterinary experts took the stageto discuss information available aboutspontaneous progressive fibrotic lung

disorders in domestic animals. Althoughsuch diseases have been recognized for20 years in horses, they have only morerecently been described in dogs and cats(6, 7, 9–12). As in human medicine, thecauses and factors associated with thesedisorders remain largely unknown.A gammaherpes virus, equine herpesvirus-5(EHV-5), has been associated with a formof progressive lung fibrosis in adulthorses. This finding may substantiatea role for gammaherpes viruses in lungfibrosis in humans, where Epstein-Barrvirus is suggested to be a cofactor inthe onset and/or progression of thedisease (13).

In humans, the diagnosis of IPF andrelated fibrosing interstitial lung diseasesdepends on a well-characterized clinical-radiographic-pathologic presentation(Figure 1); such an approach is currentlynot developed in veterinary medicinebecause the necessary prospective clinical-radiographic-pathology studies have notbeen performed. In spite of this, veterinarymedicine has borrowed terminology(i.e., IPF) from human medicine withouthaving undergone the rigorous (andsometimes rancorous) debate and researchthat has occurred in human medicine.Naturally, this has led to some confusionwhen classifying these diseases in domesticanimals. Regardless, it became apparent

throughout the meeting that the fibrosinglung diseases found in dogs, cats, andhorses share several features in commonwith human IPF. For example, as inhumans, the disease is diagnosed in middle-aged to old animals and is usually notdetected until the disease is relativelyadvanced. Also, they are all progressivediseases that are largely poorly responsiveto available therapies and usually lead to thedeath of the animal from respiratory failure.The prevalence of these disorders in eachspecies is unknown. In cats and horses,there are no readily identifiable genetic(breed) predilections. In contrast, WestHighland White Terriers, as well as otherterrier breeds, develop fibrosing idiopathicinterstitial lung disease more commonlythan other breeds (10, 11, 14).

The pathophysiology of spontaneousprogressive fibrosing lung disease indomestic animals is poorly characterizedand has been evaluated in a limited way onlyin dogs (15, 16). These few studies highlightthe need for standardized approaches toevaluate and follow the course of theselung diseases in domestic animals.Unfortunately, physiologic testing toevaluate restrictive lung disease, such asFVC, is difficult to perform in nonhumananimals due to difficulties with patientcooperation. Thoracic imaging, especiallyhigh-resolution computed tomography, has

Table 1. Methodology

Methods Checklist Yes No

Panel assemblyIncluded experts from relevant clinical andnonclinical fields

x

Included individuals who represented patientsand society at large

x

Included methodologist with appropriateexpertise

NA*

Literature reviewPerformed in collaboration with a librarian XSearch multiple electronic databases xReviewed reference list of retrieved articles x

Evidence synthesisApplied preselected inclusion and exclusioncriteria

X

Evaluated included articles for source bias XExplicitly summarized benefits and harms xUsed PRISMA1 to report systematic review NA*Used GRADE to describe quality evidence NA*

Generation of recommendationsUsed GRADE to rate the strength ofrecommendations

NA*

Definition of abbreviations: GRADE = Grades of Recommendation Assessment, Development, andEducation; PRISMA1 = Preferred Reporting Items for Systematic Reviews and Meta-Analyses 1.*Not required for workshop reports.

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been performed in cats and dogs withsuspected diffuse parenchymal lung disease(Figure 2) and in rodents, but detailedprospective studies are lacking in anynonhuman species (17). In dogs, ground-glass opacification and traction bronchiectasishave been identified (Figure 3).

Similar needs for prospectiveinvestigations were identified regarding thehistologic characterization of these

disorders in nonhuman animals. Importantcorrelates with the usual interstitialpneumonia (UIP) histologic pattern, thecharacteristic pattern observed in humanIPF, have been reported in domesticanimals. Such important correlatesinclude subpleural involvement, minimalcellular inflammation, the presence ofmyofibroblasts, temporal heterogeneityof fibrosis with evidence of ongoing

fibroproliferation, regions reminiscent of“fibroblast foci,” and the formation of“honeycomb” lung (12) (Figure 4).Unfortunately, the establishment of clearhistologic criteria to facilitate distinguishingdiffering patterns of interstitial lung diseaseand correlating them with the clinicalpresentation and outcomes, (a criticaladvance in our understanding of human IIP[18]), are missing in nonhuman mammals.

Figure 1. Computed tomography (CT) image and histology of idiopathic pulmonary fibrosis (IPF). (A) CT image of normal human lung. (B) CT imageof subject with IPF. Note infiltrates predominating in the lower lobes posteriorly with evidence of honeycombing (arrow) and traction bronchiectasis(arrowhead) with absence of pleural abnormalities. (C ) Tissue section of lung obtained from subject with IPF. Note normal alveolar spaces (star) adjacentto fibrotic tissue and areas of honeycombing (#).

Figure 2. Chest computed tomography (CT) imaging of animals. (A, B) Chest CT image in cat with lung fibrosis. (C, D) CT image in dog with lung fibrosis.

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The progressive nature of these diseasesin domestic animals and their lack ofresponse to therapeutic intervention areimportant features that are not present inconventional experimental animal modelsof pulmonary fibrosis. At the meeting,significant emphasis was put on thelimitations of our current treatmentstrategies and the lack of progress in thisarea in both IPF and lung fibrosis in animals.Corticosteroids, which have been often usedfor the treatment of IPF despite the lackof supporting data, are also often tried inanimals, with variable and generally limitedsuccess. Formal trials in domestic animalshave not been conducted with this or anyother agents recently tested in IPF.

Research Recommendations

Considering the above, the group generatedresearch recommendations that we hopewill help guide investigators interested inusing comparative biology to acceleratemeaningful discoveries in this field. Theserecommendations can be summarized asfollows:

d Detailed descriptive studies should beconducted in affected domestic animalsto define the clinical, imaging, andpathological presentation of pulmonaryfibrosis in these species.

d Genetic studies and other pathogenesis-based investigations should be conductedin naturally occurring spontaneousmodels of pulmonary fibrosis toinvestigate the potential translation toIPF in humans. These models shouldprovide more relevant tools to investigatethe potential effectiveness of novelantifibrosis drugs in prehuman trials.

d Studies should be conducted to define theanatomical and cellular differences in thelungs of different species for the adequateinterpretation of discordant findings.

d Suitable reagents needed to adequatelytest hypotheses in different species ofanimals should be generated.

d A consortium of interested centers anda central repository of clinicalinformation and biologic specimens fromnaturally occurring spontaneous modelsof lung fibrosis in domestic animalsshould be established to enable furtherresearch that may benefit both physicians

and veterinarians in their efforts toadequately manage lung fibrosis in theirpatient populations.

d Another workshop including physician andveterinary experts, pathologists, communityadvocates, and representatives of privatefoundations, industry and biotechnology,and federal scientific organizations shouldbe conducted to define specific hypothesesto be tested across species and theapproaches to be used.

Summary

Comparative medicine is a well-establisheddiscipline in which diseases encountered innonhuman animals offer powerful clues forunderstanding diseases that also affecthumans (19). It is our hope that by takingsuch an approach, and by implementing theabove recommendations, we will advanceour understanding of IPF, lung fibrosis, andlung disorders in general. The sequencingof many of the companion animal genomesand the significant conservation of thegenome among mammals should allow

Figure 3. Chest computed tomography (CT) imaging in canine lung fibrosis. (A) Normal CT image. (B) CT image showing ground-glass opacification. (C )Severe fibrosis with traction bronchiectasis.

Figure 4. Histology of lung fibrosis in animals on post mortem examination. (A) Equine pulmonary fibrosis. Note nodular interstitial and alveolarinflammation. (B) Feline pulmonary fibrosis showing subpleural localization, temporal heterogeneity, and honeycomb lung formation. (C ) Canine pulmonaryfibrosis developing subpleurally but lacking obvious temporal heterogeneity. Honeycomb lung formation not present.

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investigators to go beyond clinicalobservations within this field and supportfindings with genetic and molecular data.By examining the natural progression ofthese spontaneous diseases in animals, ourunderstanding of complex diseases and thedevelopment of therapeutic interventions islikely to be accelerated (20). It is expectedthat collaborative efforts between humanand veterinary clinicians and researcherswill ultimately provide new insights andadvance scientific knowledge in ways thatwill allow for the prevention, treatment andimproved outcome in fibrotic lung disordersin humans and domestic animals. n

This official statement was prepared by an ad hocsubcommittee of the ATS Assembly onRespiratory Cell and Molecular Biology.

Members of the Writing Group:Jesse Roman, M.D. (Chair)Kevin K. Brown, M.D.Amy Olson, M.D.BrendanM. Corcoran, M.V.D., PH.D., M.R.C.V.S.Kurt J. Williams, D.V.M., PH.D.

Author Disclosures: J.R. reported serving onan advisory committee for Boehringer Ingelheim($5,000–24,999), and research support fromFibrogen ($25,000–49,999), ImmuneWorks($25,000–49,999), and Intermune ($50,000–99,999). K.K.B. reported serving on advisory

committees of Actelion ($5,000–24,999),Boehringer Ingelheim ($5,000–24,999), Celgene($1–4,999), Centocor ($1–4999), Fibrogen ($1–4,999), Genentech ($1–4,999), GeNO (nopayments received), Gilead ($5,000–24,999),Medimmune ($1–4,999), Mesoblast ($1–4,999),Promedior ($1–4,999), and Stromedix/Biogen($1–4,999); he reported consulting for Almirall($1–4,999), Amgen ($1–4,999), Array Biopharm($1–4,999), Genzyme (no payments received),GlaxoSmithKline (no payment received), Ikaria($1–4,999), Ironwood ($1–4,999), and Pfizer (nopayment received); he received research supportfrom Actelion ($100,000–249,999), Amgen($25,000–49,999), Genentech ($25,000–49,999), and Gilead ($5,000–24,999). K.J.W.reported research support from Pfizer AnimalHealth ($5,000–24,999). A.O. and B.M.C.reported that they had no relevant commercialinterests.

Indiana Meeting Participants:Teresa Barnes, Coalition of Pulmonary Fibrosis,Chicago, IL; Kevin K. Brown, M.D., Departmentsof Medicine, National Jewish Health andUniversity of Colorado School of Medicine,Denver, CO; Brendan M. Corcoran, M.V.D.,PH.D., M.R.C.V.S., Division of Veterinary ClinicalStudies, Royal (Dick) School of VeterinaryStudies and Roslin Institute, Roslin, Midlothian,Scotland, UK; Laurent L. Couetil, D.V.M., PH.D.,Purdue University School of Veterinary Medicine,West Lafayette, IN; Margareta K. Eriksson,PH.D., Department of Anatomy, Physiology, andBiochemistry, Swedish University of Agricultural

Sciences, Uppsala, Sweden; ChristineHaakenson, PH.D., AKC Canine HealthFoundation, Raleigh, NC; Wayne Kompare,Westie Foundation of America, Inc.; Keith Meyer,M.D., Department of Medicine, University ofWisconsin, Madison, WI; Tobie McPhail; AmyOlson, M.D., Departments of Medicine, NationalJewish Health and University of Colorado Schoolof Medicine, Denver, CO; David Perlman, M.D.,Department of Medicine, University of Minnesota,Minneapolis, MN; Elizabeth Rozanski, D.V.M.,Department of Clinical Sciences, CummingsSchool of Veterinary Medicine, Tufts University,North Grafton, MA; A. Tidwell, D.V.M.; RichardVulliet, D.V.M., PH.D., Department of VeterinaryMolecular Biosciences, UC Davis, Davis, CA;Timothy Weaver, PH.D., Division of PulmonaryBiology, Cincinnati Children’s ResearchFoundation, Cincinnati, OH; Erika Werne, M.S.,AKC Canine Health Foundation, Raleigh, NC;Kurt Williams, D.V.M., PH.D., Department ofPathobiology, College of Veterinary Medicine,Michigan State University, East Lansing, MI; JesseRoman, M.D., Department of Medicine, Universityof Louisville, Louisville, KY.

Acknowledgment: The authors thank theWestieFoundation of America, Inc. for leading the way toa better understanding of lung fibrosis throughcomparative biology, and the American ThoracicSociety for supporting the RCMB Working Groupand for defraying the cost of publication. They alsothank Elizabeth Rozanski (Tufts University) forproviding images related to dogs and cats.

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