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Original Research: Diffuse Lung Disease |

Chronic Pleuropulmonary Fibrosis and Elastosis of Aged DonkeysChronic Pleuropulmonary Fibrosis of Aged Donkeys: Similarities to Human Pleuroparenchymal Fibroelastosis FREE TO VIEW

Amy Miele, BVM&S; Kevin Dhaliwal, MBChB, PhD; Nicole Du Toit, BVSc, PhD; John T. Murchison, MBChB, PhD; Catharine Dhaliwal, MBChB, PhD; Harriet Brooks, BVetMed, PhD; Sionagh H. Smith, BVMS, PhD; Nik Hirani, MBChB, PhD; Tobias Schwarz, DrMedVet; Chris Haslett, MBChB; William A. Wallace, MBChB, PhD; Bruce C. McGorum, BVM&S, PhD
Author and Funding Information

From the Medical Research Council Centre for Inflammation Research (Drs Miele, K. Dhaliwal, and Hirani and Prof Haslett), Queen’s Medical Research Institute, and Royal (Dick) School of Veterinary Studies and The Roslin Institute (Drs Smith and Schwarz and Prof McGorum), University of Edinburgh, Edinburgh, Scotland; The Donkey Sanctuary (Drs Du Toit and Brooks), Sidmouth, Devon, England; and Department of Radiology (Dr Murchison) and Department of Pathology (Drs C. Dhaliwal and Wallace), New Edinburgh Royal Infirmary, Edinburgh, Scotland.

Correspondence to: Bruce C. McGorum, BVM&S, PhD, The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Scotland, EH259RG; e-mail: bruce.mcgorum@ed.ac.uk


Drs Miele, K. Dhaliwal, and Wallace and Prof McGorum contributed equally.

Part of this article was presented in abstract form at the British Society of Animal Science Annual Meeting, April 16-17, 2013, Nottingham, England, and at the 7th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland, June 18-21, 2013, Edinburgh, Scotland.

Funding/Support: This study was funded by the Medical Research Council (MR/J014702/1).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1325-1332. doi:10.1378/chest.13-1306
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Background:  Donkey pulmonary fibrosis (DPF) is a spontaneous syndrome of aged donkeys with a high prevalence (35%). No previous detailed characterization of DPF has been performed. We sought to determine the similarities between DPF and recognized patterns of human pulmonary fibrosis.

Methods:  Whole lungs were collected from 32 aged donkeys at routine necropsy. Gross examination revealed pulmonary fibrosis in 19 donkeys (DPF cases), whereas 13 (control cases) had grossly normal lungs. Eighteen whole inflated ex vivo lungs (11 DPF cases, seven control cases) were imaged with high-resolution CT (HRCT) scan, whereas the remainder were sectioned and photographed. Tissue samples were collected from all lungs for histopathologic evaluation using a standardized protocol. HRCT images and histology sections underwent independent blinded review. Lung tissue was analyzed for herpes virus, fungal hyphae, mycobacteria, and dust content.

Results:  Ten of 19 DPF lungs were categorized as being consistent with pleuroparenchymal fibroelastosis (PPFE) according to previously defined histologic and imaging criteria. All 10 PPFE-like lungs had marked pleural and subpleural fibrosis, predominantly within the upper lung zone, with accompanying intraalveolar fibrosis and elastosis. Asinine herpesvirus was ubiquitously expressed within control and DPF lung tissue. No other etiologic agents were identified.

Conclusions:  Many cases of DPF share key pathologic and imaging features with human PPFE, a rare interstitial pneumonia. Consequently, further study of DPF may help to elucidate the etiopathogenesis of human PPFE.

Figures in this Article

Pulmonary fibrosis represents the end point of many diseases and is characterized by excessive and irreversible deposition of extracellular matrix in the lung parenchyma, leading to compromised ventilation and organ dysfunction. Despite considerable research, many fibrotic lung diseases remain elusive in terms of etiology, pathogenesis, and treatment.1 Progress is hindered by the lack of a translatable animal model with durable and persistent fibrosis.2

The term “idiopathic pleuroparenchymal fibroelastosis” was coined by the authors of a case study in 2004 to describe a novel clinicopathologic entity that did not fall within the 2002 American Thoracic Society consensus classification of idiopathic interstitial pneumonias.3 The authors described a predominantly upper zone distribution of pleural and subpleural fibrosis with elastosis and proposed that previous reports of idiopathic pulmonary fibrosis of upper lung lobes were consistent with pleuroparenchymal fibroelastosis (PPFE).3 PPFE was subsequently included in the 2013 American Thoracic Society/European Respiratory Society statement “Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias” in the category of rare idiopathic interstitial pneumonias.4 Although PPFE is regarded as usually idiopathic, it has been linked with connective tissue diseases, genetic predisposition, and autoimmunity following organ transplant.35 Reddy et al5 suggested that repeated inflammatory damage following recurrent infections in predisposed individuals could lead to PPFE and that airway-centered injury could be key to disease pathogenesis.

Donkey pulmonary fibrosis (DPF) is a syndrome that is also sparsely documented, yet a prevalence of 35% at routine necropsy was reported in a UK cohort.6 Very little is known about this chronic, potentially debilitating, and currently untreatable idiopathic condition. To test our hypothesis that many cases of DPF share the key pathologic and imaging characteristics of PPFE, we performed the most comprehensive systematic characterization of DPF to date.

Tissue Collection and Processing

Whole lungs were collected from 32 aged donkeys during routine necropsy at two UK donkey sanctuaries between June 2009 and January 2013 (e-Appendix 1). Nineteen DPF lungs were selected because of grossly visible fibrosis, whereas 13 grossly unaffected control lungs were selected at random. All lungs were manually inflated, the tracheas clamped, and gross images photographed. Tissue samples were collected from each lung into 10% buffered formalin, essentially as described previously,7 before undergoing routine processing to paraffin blocks. Sections were stained with hematoxylin and eosin, elastic Van Gieson (EVG), and Masson’s trichrome. Tissue samples from eight lungs (four DPF, four control) were collected into RNAlater (QIAGEN) for DNA extraction and subsequent polymerase chain reaction (PCR). Because this study used only ex vivo tissue collected at routine necropsy, licensing on ethical and humane grounds was not required.

Histology

Histology sections were reviewed independently and blindly by three medical and veterinary pathologists with experience in lung disease. Subsequent to the recognition that the changes observed resembled those of human PPFE, the histologic features were categorized as being consistent with or inconsistent with PPFE according to criteria described by Reddy et al.5 Cases were categorized as consistent with PPFE on histology if (1) there was pleural thickening with associated subpleural intraalveolar fibrosis and alveolar septal elastosis or (2) intraalveolar fibrosis was present but either not associated with pleural fibrosis, not predominantly subpleural, or not in a dorsal lobe sample. Inconsistent with PPFE was assigned to lungs that lacked these features.

High-Resolution CT Imaging and Digital Photography

Eighteen whole inflated ex vivo lungs (11 DPF, seven control) were imaged with a high-resolution CT (HRCT) scanner (Aquilion One [Toshiba Medical Systems, Toshiba Corp] or Somatom Volume Zoom [Siemens AG]). The remaining lungs (eight DPF, six control) were systematically sectioned transversely and photographed digitally. All images were reviewed independently and blindly by an expert radiologist and were categorized as consistent with or inconsistent with PPFE according to criteria described previously.5 Cases were categorized as consistent with PPFE if (1) there was pleural thickening with associated subpleural fibrosis predominantly in the dorsal lung or (2) there was dorsal lung pleural thickening and associated subpleural fibrosis, but the distribution of fibrosis was not concentrated in the dorsal lung or coexistent lung disease was evident elsewhere. Inconsistent with PPFE was assigned to lungs that lacked these features. Overall, cases were assigned as PPFE-like only if categorized as consistent with PPFE on both imaging and histology.

PCR for Herpesviral Polymerase

Eight lung samples (four DPF, four control) collected into RNAlater were processed using an AllPrep DNA/RNA Mini Kit (QIAGEN) according to the manufacturer’s instructions. For investigation of the presence of herpesvirus, a region of the herpesvirus DNA polymerase gene was amplified using 100 ng DNA per reaction with two sets of nested degenerate primers as previously described.8 PCR products were cloned into the TOPO TA vector (Invitrogen by Life Technologies) and sequenced (The GenePool), and BLASTn, version 2.6.2 (National Center for Biotechnology Information) was used to align derived sequences against known herpesvirus sequences.

Special Staining

Lung sections in which there was granulomatous inflammation were stained for acid-fast bacteria using a standard Ziehl-Neelsen stain and for fungal hyphae using Grocott’s methenamine silver and periodic acid-Schiff stains.

X-ray Diffraction

Formalin-fixed wet lung tissue samples from four DPF ex vivo lungs were pooled, digested in potassium hydroxide, and prepared for mineral particle analysis under transmission electron microscopy at a magnification of 20,000 and for energy-dispersive x-ray analysis. The mass of dust per gram of dry lung tissue was established. Both fibrous and nonfibrous particles were counted and typed.

Ages were not significantly different between DPF (median, 31 years; range, 14-53 years) and control (median, 28 years; range, 4-36 years) donkeys at necropsy (Mann-Whitney P > .05). The average donkey lifespan is 30 years. Donkeys comprised 12 neutered males and 20 females (e-Table 1).

Ten of 19 DPF lungs were categorized as being PPFE-like, having features consistent with PPFE on both pathology (Table 1) and imaging (seven on HRCT scan and three on photographed images of sectioned lungs). All 10 PPFE-like lungs had grossly visible visceral pleural fibrosis on the dorsal/costal surface, with no involvement of the parietal pleura. This was characterized by multifocal-to-coalescing vermiform cream/gray lesions that caused visible restriction of pleural expansion on manual lung inflation (Fig 1, e-Fig 1). Because donkeys are quadrupeds, the dorsal lung equates to the human lung upper zone. Histologically, all 10 PPFE-like lungs had dorsal pleural and subpleural fibrosis, with subpleural intraalveolar fibrosis and elastosis evident on EVG-stained sections (Figs 2AD). Spatial heterogeneity was a consistent feature, often with a sharp interface between fibrotic and adjacent normal tissue (Fig 2E). Other common features (Table 2) included septal and bronchiolocentric fibrosis, lymphoplasmacytic bronchiolitis, granulomatous inflammation, and vascular remodeling within areas of fibrosis (Figs 2FH). Honeycombing and fibroblastic foci were not detected, although myofibroblasts were demonstrated within fibrotic lesions through α-smooth muscle actin immunohistochemistry (e-Fig 2).

Table Graphic Jump Location
Table 1 —Classification of Ex Vivo Donkey Lungs

HRCT = high-resolution CT.

Figure Jump LinkFigure 1. A and B, Photographs of the dorsal (uppermost) surface of inflated ex vivo control (A) and pleuroparenchymal fibroelastosis-like (B) lungs. C, Where high-resolution CT scan was not available, lungs were sectioned vertically prior to digital imaging. Note the extensive dorsal pleural fibrosis in B and C.Grahic Jump Location
Figure Jump LinkFigure 2. Histology images of sections from pleuroparenchymal fibroelastosis (PPFE)-like donkey lungs. A, Pleural and subpleural fibrosis with alveolar septal elastosis and intraalveolar fibrosis (elastic Van Gieson [EVG]). B, Disarray of the pleural elastin with a band of fibrosis extending from the subpleura along an interlobular septum (EVG). C, Higher-powered view of an area of intraalveolar fibrosis (EVG). D, High-power view of an area of diffuse elastosis (EVG). E-H, Other common histologic features of the PPFE-like ex vivo donkey lungs include spatial heterogeneity (EVG) (E), aggregates of mononuclear inflammatory cells (hematoxylin and eosin [H&E]) (F), bronchiolocentric inflammation and fibrosis (H&E) (G), and intimal fibrosis and elastosis of entrapped vessels (EVG) (H). I and J, Sections of donkey pulmonary fibrosis tissue classified as inconsistent with PPFE (H&E), demonstrating intraalveolar inflammation and fibrin deposition (I) and fibrosis of the alveolar walls with conservation of alveolar architecture (J).Grahic Jump LocationGrahic Jump Location
Table Graphic Jump Location
Table 2 —Frequency of Imaging and Histologic Features Identified in Ex Vivo PPFE-Like Donkey Lungs

PPFE = pleuroparenchymal fibroelastosis.

All seven PPFE-like lungs imaged by HRCT scan had pleuroparenchymal thickening (maximum, 5-32 mm) of the dorsal lung lobes, with associated subpleural consolidation consistent with established fibrosis. The consolidation extended from the subpleural region along parenchymal bands (Fig 3). In two of the seven lungs, the fibrosis was relatively superficial and confined solely to the uppermost zones of the dorsal lung surface. The other five cases had consolidation extending along parenchymal bands into mid and ventral zones that often radiated out to surround adjacent bronchi. Features of coexistent disease identified on HRCT scan included primary bronchiectasis and ground glass opacity. Traction bronchiectasis was present to varying degrees in all seven cases (Table 2). Ground glass change was a feature in four of the seven PPFE-like lungs, although some of this was attributed to collapse of dependent parenchyma in the inflated ex vivo tissue, a feature also noted in three of the seven control lungs.

Figure Jump LinkFigure 3. Craniocaudal high-resolution CT images of PPFE-like inflated ex vivo donkey lungs. A-C, Pathology ranged from mild dorsal pleural fibrosis extending along parenchymal bands (A) to thick rinds of pleural fibrosis encasing the dorsal surface of the lung (B and C). Also note the traction bronchiectasis (large arrow) and bronchocentric fibrosis (small arrow). See Figure 2 legend for expansion of abbreviation.Grahic Jump Location

All nine DPF lungs classified as inconsistent with PPFE on histology had pleural, subpleural, or septal fibrosis in at least one section. In four of these lungs, the fibrosis was focused around alveolar walls, with similarities to a nonspecific interstitial pneumonia-type pattern (Fig, 2I, 2J). Importantly, all nine lungs lacked the intraalveolar fibrosis previously reported to be a feature of PPFE,5 but the majority (seven) had marked intraalveolar mononuclear cell infiltrates with fibrin deposition.

Four of the 19 lungs were classified as inconsistent with PPFE on imaging (two on HRCT scan and two on photographic imaging). Two of these had small amounts of dorsal pleural and subpleural fibrosis that were either asymmetric or considered not to be a predominant feature. One had a predominantly ventral distribution of fibrosis, whereas the other showed diffuse ground glass opacity (Fig 4).

Figure Jump LinkFigure 4. High-resolution CT images of fibrotic inflated ex vivo donkey lungs classified as inconsistent with PPFE on both imaging and histology. A and B, These images show a predominantly ventral distribution to the fibrosis. C, Image demonstrates diffuse ground glass change. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location

Acid-fast bacteria and fungi were not identified with special staining. Herpesviral sequences were identified in six of eight lung homogenates, with five mapping to asinine herpesvirus (AsHV)-5 and one to AsHV-4. X-ray diffraction analysis revealed a dust burden of 6.98 mg/g dry lung. Small numbers of fibrous particles were identified (talc, 0.28 million fibers/g dry lung; silica, 0.14 million fibers/g dry lung). The percentages of nonfibrous particles were calcium silicate, 95%; potassium silicate, 2%; kaolin, 1%; muscovite, 1%; and silica, 1%. No asbestos fibers were found.

To our knowledge, this study is the most comprehensive of a spontaneous large animal model of pulmonary fibrosis to date. Although the donkey may seem an implausible candidate with which to share pathologic features of pulmonary disease, of all the domestic species, the subgross anatomy of the equine lung and visceral pleura most closely resembles that of humans.9

DPF was first reported as a common incidental necropsy finding of donkeys resident at a donkey sanctuary in 2001.10 Reported gross and histopathologic findings were consistent with those for the current study, including a wide spectrum of pleural, subpleural, and septal fibrosis extending into the interstitium of dorsal lung fields, with more diffuse and ventral changes in severely affected cases. Peribronchial cuffing and multifocal aggregates of mononuclear cells were also described.10 However, the presence of intraalveolar fibrosis and alveolar septal elastosis was not reported, probably because these features are less striking in the absence of EVG staining. It should be noted that fibroblastic foci and honeycombing are not features of DPF.

In the current study, > 50% of donkeys with DPF shared key imaging and pathologic characteristics of human PPFE. DPF lungs were classified as PPFE-like only if they had features considered consistent with PPFE3 on both histology and imaging. In this respect, a greater proportion of DPF lungs were classified as consistent with PPFE on HRCT scan (82%) compared with histology (58%). It is possible that some of the nine lungs classified as inconsistent with PPFE on histology represent an earlier stage of PPFE-like disease. Seven of these had intraalveolar mononuclear inflammatory infiltrates with organizing intraalveolar fibrin, which is a likely prelude to intraalveolar fibrosis (Fig 2I). Furthermore, the marked spatial heterogeneity in extent and pattern of fibrosis means that PPFE-like pathology may have been missed as a result of unrepresentative sampling in some cases.

Imaging of PPFE-like lungs indicated that although all had the characteristic predominantly dorsal distribution of lesions, seven of the 10 lungs also had pleural and subpleural fibrosis in the mid and ventral pulmonary parenchyma. Similarly, Reddy et al5 reported that six of 12 PPFE lungs had interstitial lung disease in lobes distant from the upper zone on HRCT scan. Furthermore, six of the 12 PPFE lungs had areas of consolidation, and one of the 12 had bronchiectasis. In the present study, HRCT scans showed ground glass opacity in four of seven PPFE-like lungs and traction bronchiectasis in all seven. The presence of bronchocentric consolidation on HRCT images of five of these seven lungs further supports the proposal that chronic airway disease could be key to PPFE pathogenesis.5 Bronchocentric changes were also evident histologically, with all 10 PPFE-like lungs having variable lymphoplasmacytic bronchiolitis and eight of the 10 having areas of bronchocentric fibrosis. A patchy lymphoplasmacytic infiltrate was a feature in patients with PPFE reported by Frankel et al,3 whereas Reddy et al5 found bronchocentric fibrosis in 11 of 12 patients with PPFE, with all 12 having focal nonspecific chronic inflammation with lymphoid follicle accumulation.

Other features of PPFE shared by donkey PPFE-like lungs included perilobular fibrosis (all 10) and venous and arterial intimal fibrosis (nine of 10).5,11 Vascular changes in donkey lungs were considered to reflect secondary intimal invasion by the surrounding fibrosis rather than a primary vasculopathy. Although granulomatous inflammation is not a key accepted feature of PPFE, it has been detected in patients with PPFE5 and was an additional feature of three of the 10 PPFE-like lungs in the current study. However, mycobacteria and fungi were not identified in the granulomatous lesions. Pleural fibrosis is a feature of asbestos-induced pulmonary fibrosis12 in humans. Inorganic fiber content of the ex vivo donkey lung tissue was minimal, and there was no evidence of asbestos fibers. The presence of nonfibrous dust particles, such as calcium silicate, was unsurprising considering the grazing habits of donkeys and likely reflected local soil composition. Potential toxicity of calcium silicate is believed to be minimal,13 and the dust burden of ex vivo donkey tissue was not considered to be significant.

The significance of elastosis within fibrotic donkey tissue is unclear. Elastosis and upregulation of elastin gene expression occurs in a murine model of pulmonary fibrosis,14 and in humans, progressive vascular fibroelastosis occurs in idiopathic interstitial pneumonias and correlates with a poor prognosis in usual interstitial pneumonia.15 An overall increase in both collagen and elastin with alveolar septal elastosis has been documented during the late phase of ARDS and in usual interstitial pneumonia.16

Reddy et al5 reported that seven of 12 patients with PPFE had a history of recurrent lower respiratory tract infections, leading these authors to postulate the contribution of such infections to the pathogenesis of PPFE. Further investigation is required to determine whether donkeys with PPFE-like disease had preceding recurrent lower respiratory tract infections (e-Table 1, e-Fig 1).

In the horse, a progressive fibrosing interstitial lung disease termed “equine multinodular pulmonary fibrosis” is associated with equine herpesvirus 5 infection.17 Similarly, AsHV-4 and AsHV-5 were implicated in an acute fibrosing interstitial pneumonia in 11 donkeys in North America and in a pyogranulomatous pneumonia in a mare.8,18 Kleiboeker et al8 described multifocal-to-coalescing nodules of fibrosis scattered throughout the lung parenchyma in the most severely affected of the 11 donkeys, a pattern similar to that seen in equine multinodular pulmonary fibrosis and quite different from the pathology described herein for DPF. Kleiboeker et al8 also detected herpesviral DNA in lung homogenate in all 11 affected donkeys but not in six control animals, which differs from the current findings that lung homogenates from all DPF and control donkeys were positive for AsHV-4 or AsHV-5. The role of AsHV-4 and AsHV-5 in DPF warrants further study.

In conclusion, > 50% of donkeys with DPF in this study shared key imaging and pathologic characteristics of human PPFE, a rare and usually idiopathic interstitial pneumonia.4 Hence, the donkey may provide a unique progressive model in which to study PPFE. The ubiquitous presence of γ-herpesvirus in the study population of donkeys warrants further investigation regarding its potential role in the etiology of DPF.

Author contributions: Drs Miele, K. Dhaliwal, and Wallace and Prof McGorum had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Miele: contributed to the data collection and writing of the manuscript.

Dr K. Dhaliwal: contributed to the study concept, overall guidance, and writing of the manuscript.

Dr Du Toit: contributed to the tissue collection and review of the manuscript for important intellectual content.

Dr Murchison: contributed to the imaging data description, assessment, and scoring and review of the manuscript for important intellectual content.

Dr C. Dhaliwal: contributed to the scoring of histology data and review of the manuscript for important intellectual content.

Dr Brooks: contributed to the tissue collection and review of the manuscript for important intellectual content.

Dr Smith: contributed to the histology description and review of the manuscript for important intellectual content.

Dr Hirani: contributed to the review of the manuscript for important intellectual content.

Dr Schwarz: contributed to the HRCT scanning and review of the manuscript for important intellectual content.

Prof Haslett: contributed to the review of the manuscript for important intellectual content.

Dr Wallace: contributed to the study concept; histology data description, assessment, and scoring; and review of the manuscript for important intellectual content.

Prof McGorum: contributed to the study concept, overall guidance, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors thank R. Dalziel, BSc, PhD, The Roslin Institute & R(D)SVS, University of Edinburgh, for performing DNA extraction and herpesviral PCR; A. R. Gibbs, MBChB, Environmental Lung Disease Research Group, University Hospital Llandough, Penarth, for performing x-ray diffraction analysis; and the Clinical Research Imaging Centre, University of Edinburgh, for conducting HRCT scans.

Additional information: The e-Appendix, e-Figures, and e-Table can be found in the “Supplemental Materials” area of the online article.

AsHV

asinine herpesvirus

DPF

donkey pulmonary fibrosis

EVG

elastic Van Gieson

HRCT

high-resolution CT

PCR

polymerase chain reaction

PPFE

pleuroparenchymal fibroelastosis

Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol. 2005;33(1):9-13.
 
Williams K, Malarkey D, Cohn L, Patrick D, Dye J, Toews G. Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology and ultrastructural evidence for a type II pneumocyte defect. Chest. 2004;125(6):2278-2288.
 
Frankel SK, Cool CD, Lynch DA, Brown KK. Idiopathic pleuroparenchymal fibroelastosis: description of a novel clinicopathologic entity. Chest. 2004;126(6):2007-2013.
 
Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748.
 
Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012;40(2):377-385.
 
Morrow LD, Smith KC, Piercy RJ, et al. Retrospective analysis of post-mortem findings in 1,444 aged donkeys. J Comp Pathol. 2011;144(2-3):145-156.
 
Williams KJ, Derksen FJ, de Feijter-Rupp H, Pannirselvam RR, Steel CM, Robinson NE. Regional pulmonary veno-occlusion: a newly identified lesion of equine exercise-induced pulmonary hemorrhage. Vet Pathol. 2008;45(3):316-326.
 
Kleiboeker SB, Schommer SK, Johnson PJ, et al. Association of two newly recognized herpesviruses with interstitial pneumonia in donkeys (Equus asinus). J Vet Diagn Invest. 2002;14(4):273-280.
 
McLaughlin RF Jr, Tyler WS, Canada RO. Subgross pulmonary anatomy in various mammals and man. JAMA. 1961;175(8):694-697.
 
Thiemann A, Bell N. The peculiarities of donkey respiratory disease.. In:Lekeux P., ed. Equine Respiratory Disease [serial online]. International Veterinary Information Service website. http://www.ivis.org/special_books/Lekeux/bell/ivis.pdf. Accessed January 20, 2011.
 
Piciucchi S, Tomassetti S, Casoni G, et al. High resolution CT and histological findings in idiopathic pleuroparenchymal fibroelastosis: features and differential diagnosis. Respir Res. 2011;12:111.
 
Bergin CJ, Castellino RA, Blank N, Moses L. Specificity of high-resolution CT findings in pulmonary asbestosis: do patients scanned for other indications have similar findings? AJR Am J Roentgenol. 1994;163(3):551-555.
 
Bolton RE, Addison J, Davis JM, et al. Effects of the inhalation of dusts from calcium silicate insulation materials in laboratory rats. Environ Res. 1986;39(1):26-43.
 
Hoff CR, Perkins DR, Davidson JM. Elastin gene expression is upregulated during pulmonary fibrosis. Connect Tissue Res. 1999;40(2):145-153.
 
Parra ER, Kairalla RA, de Carvalho CRR, Capelozzi VL. Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias. Thorax. 2007;62(5):428-437.
 
Negri EM, Montes GS, Saldiva PH, Capelozzi VL. Architectural remodelling in acute and chronic interstitial lung disease: fibrosis or fibroelastosis? Histopathology. 2000;37(5):393-401.
 
Williams KJ, Maes R, Del Piero F, et al. Equine multinodular pulmonary fibrosis: a newly recognized herpesvirus-associated fibrotic lung disease. Vet Pathol. 2007;44(6):849-862.
 
De Witte FG, Frank N, Wilkes RP, Novak JM. Association of asinine herpesvirus-5 with pyogranulomatous pneumonia in a mare. J Vet Intern Med. 2012;26(4):1064-1068.
 

Figures

Figure Jump LinkFigure 1. A and B, Photographs of the dorsal (uppermost) surface of inflated ex vivo control (A) and pleuroparenchymal fibroelastosis-like (B) lungs. C, Where high-resolution CT scan was not available, lungs were sectioned vertically prior to digital imaging. Note the extensive dorsal pleural fibrosis in B and C.Grahic Jump Location
Figure Jump LinkFigure 2. Histology images of sections from pleuroparenchymal fibroelastosis (PPFE)-like donkey lungs. A, Pleural and subpleural fibrosis with alveolar septal elastosis and intraalveolar fibrosis (elastic Van Gieson [EVG]). B, Disarray of the pleural elastin with a band of fibrosis extending from the subpleura along an interlobular septum (EVG). C, Higher-powered view of an area of intraalveolar fibrosis (EVG). D, High-power view of an area of diffuse elastosis (EVG). E-H, Other common histologic features of the PPFE-like ex vivo donkey lungs include spatial heterogeneity (EVG) (E), aggregates of mononuclear inflammatory cells (hematoxylin and eosin [H&E]) (F), bronchiolocentric inflammation and fibrosis (H&E) (G), and intimal fibrosis and elastosis of entrapped vessels (EVG) (H). I and J, Sections of donkey pulmonary fibrosis tissue classified as inconsistent with PPFE (H&E), demonstrating intraalveolar inflammation and fibrin deposition (I) and fibrosis of the alveolar walls with conservation of alveolar architecture (J).Grahic Jump LocationGrahic Jump Location
Figure Jump LinkFigure 3. Craniocaudal high-resolution CT images of PPFE-like inflated ex vivo donkey lungs. A-C, Pathology ranged from mild dorsal pleural fibrosis extending along parenchymal bands (A) to thick rinds of pleural fibrosis encasing the dorsal surface of the lung (B and C). Also note the traction bronchiectasis (large arrow) and bronchocentric fibrosis (small arrow). See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4. High-resolution CT images of fibrotic inflated ex vivo donkey lungs classified as inconsistent with PPFE on both imaging and histology. A and B, These images show a predominantly ventral distribution to the fibrosis. C, Image demonstrates diffuse ground glass change. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Classification of Ex Vivo Donkey Lungs

HRCT = high-resolution CT.

Table Graphic Jump Location
Table 2 —Frequency of Imaging and Histologic Features Identified in Ex Vivo PPFE-Like Donkey Lungs

PPFE = pleuroparenchymal fibroelastosis.

References

Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol. 2005;33(1):9-13.
 
Williams K, Malarkey D, Cohn L, Patrick D, Dye J, Toews G. Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology and ultrastructural evidence for a type II pneumocyte defect. Chest. 2004;125(6):2278-2288.
 
Frankel SK, Cool CD, Lynch DA, Brown KK. Idiopathic pleuroparenchymal fibroelastosis: description of a novel clinicopathologic entity. Chest. 2004;126(6):2007-2013.
 
Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748.
 
Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012;40(2):377-385.
 
Morrow LD, Smith KC, Piercy RJ, et al. Retrospective analysis of post-mortem findings in 1,444 aged donkeys. J Comp Pathol. 2011;144(2-3):145-156.
 
Williams KJ, Derksen FJ, de Feijter-Rupp H, Pannirselvam RR, Steel CM, Robinson NE. Regional pulmonary veno-occlusion: a newly identified lesion of equine exercise-induced pulmonary hemorrhage. Vet Pathol. 2008;45(3):316-326.
 
Kleiboeker SB, Schommer SK, Johnson PJ, et al. Association of two newly recognized herpesviruses with interstitial pneumonia in donkeys (Equus asinus). J Vet Diagn Invest. 2002;14(4):273-280.
 
McLaughlin RF Jr, Tyler WS, Canada RO. Subgross pulmonary anatomy in various mammals and man. JAMA. 1961;175(8):694-697.
 
Thiemann A, Bell N. The peculiarities of donkey respiratory disease.. In:Lekeux P., ed. Equine Respiratory Disease [serial online]. International Veterinary Information Service website. http://www.ivis.org/special_books/Lekeux/bell/ivis.pdf. Accessed January 20, 2011.
 
Piciucchi S, Tomassetti S, Casoni G, et al. High resolution CT and histological findings in idiopathic pleuroparenchymal fibroelastosis: features and differential diagnosis. Respir Res. 2011;12:111.
 
Bergin CJ, Castellino RA, Blank N, Moses L. Specificity of high-resolution CT findings in pulmonary asbestosis: do patients scanned for other indications have similar findings? AJR Am J Roentgenol. 1994;163(3):551-555.
 
Bolton RE, Addison J, Davis JM, et al. Effects of the inhalation of dusts from calcium silicate insulation materials in laboratory rats. Environ Res. 1986;39(1):26-43.
 
Hoff CR, Perkins DR, Davidson JM. Elastin gene expression is upregulated during pulmonary fibrosis. Connect Tissue Res. 1999;40(2):145-153.
 
Parra ER, Kairalla RA, de Carvalho CRR, Capelozzi VL. Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias. Thorax. 2007;62(5):428-437.
 
Negri EM, Montes GS, Saldiva PH, Capelozzi VL. Architectural remodelling in acute and chronic interstitial lung disease: fibrosis or fibroelastosis? Histopathology. 2000;37(5):393-401.
 
Williams KJ, Maes R, Del Piero F, et al. Equine multinodular pulmonary fibrosis: a newly recognized herpesvirus-associated fibrotic lung disease. Vet Pathol. 2007;44(6):849-862.
 
De Witte FG, Frank N, Wilkes RP, Novak JM. Association of asinine herpesvirus-5 with pyogranulomatous pneumonia in a mare. J Vet Intern Med. 2012;26(4):1064-1068.
 
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