a pathological study of emphysema of lungs with …thorax(1958), 13, 136. a pathological study of...

Thorax (1958), 13, 136.

A PATHOLOGICAL STUDY OF EMPHYSEMA OF THELUNGS WITH CHRONIC BRONCHITIS

BY

BRIAN E. HEARDFrom tile Department of Morbid Anatomy, Postgraduate Medical Sclhool of Lonidon

(RECEIVED FOR PUBLICATION DECEMBER 20, 1957)

The terms chronic bronchitis and emphysemahave been used together for many years, but un-less the emphysema is advanced there can be noclinical or radiological proof of its existence ina "bronchitic." Even in necropsy material thepresence of centrilobular emphysema has beenidentified only very recently (Gough, 1952;McLean, 1956a; Leopold and Gough, 1957).Fletcher (1952) points out that the objectivemethods of the physiologist can help the clinicianin his perplexity over the clinical diagnosis ofemphysema. Further work on the basic patho-logical appearances of emphysema should be ofsome assistance in interpreting physiological find-ings in chronic bronchitics.

It was decided, on these grounds, to examine aseries of lungs obtained at necropsy from patientswith clinical evidence of chronic bronchitis, usingspecial methods to demonstrate emphysema. Theseries is small and growing slowly, but since 12 ofthe first 14 cases showed widespread centrilobularemphysema, it was thought worth while to describethe methods and some of the findings to date. Aclose clinico-pathological study is the eventualaim of the work.The clinical features of chronic bronchitis have

been summarized by Scadding (1952) and byOswald, Harold, and Martin (1953). Selection ofthe present cases was based on their descriptions.

Pathologists have used unreliable signs ofemphysema in the past. Bullae are not always anindication of widespread disease and may be seenquite commonly in the upper lobes of elderlysubjects with otherwise relatively normal lungs.Bullae may be absent from lungs showing wide-spread centrilobular emphysema. Large lungsbulging from the opened thorax at necropsy indi-cate terminal bronchial obstruction which maymean acute emphysema rather than chronic. Amore reliable indication of emphysema is the soft,stringy character of the cut surface of the severely

affected lung, though this is often difficult to see.Moderate grades can be found by floating slices oflung in water and this is a useful procedure, butthe translucency of lung tissue still prevents finedetails from being recognized with conviction.The translucency of the lung can be overcome

by a simple method, described here, of impregnat-ing lung slices with barium sulphate. Fortunately,centrilobular lesions affect dust-pigmented respira-tory bronchioles, and these dark dilated bron-chioles contrast well with the barium-whitenedsurroundings. The procedure can be carried outon unfixed, or quickly-fixed, tissue at the time ofnecropsy. It is best applied to material fixed bydistension of the bronchial tree with formalin.The procedure greatly facilitates photography, asthe accompanying figures illustrate.The first essential for a reliable estimate of

emphysema is fixation of the lung with even,though gentle, distension of all air spaces. Thishas been achieved by prolonging the period of fix-ation under pressure. A simple device is describedfor applying a continuous pressure of 10 in.(25 cm.) of formalin for days or weeks at a time,and barium impregnation of slices of such materialgives reliable results.Some recent specimens have been injected

through the pulmonary arteries with a barium-gelatin mixture by Professor C. V. Harrison. Thismethod shows up the fine lobular branches of thepulmonary arteries in lung slices and demonstratesthe centrilobular distribution of lesions wheresepta are ill defined (Fig. 8). It also shows that inadvanced diffuse emphysema the arteries remainintact (Fig. 4), while the other structures of thelobule atrophy.

Focal emphysema has been described by Gough(1940) and Heppleston (1947). Recent work onnon-industrial emphysema began in 1948 with thedevelopment by Gough and Wentworth of thenow well-known method of entire-lung sections.

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EMPHYSEMA OF THE LUNGS WITH CHRONIC BRONCHITIS

In 1952 Gough divided emphysema into two varie-ties, one in which forces appeared to affect thelung as one unit and the other in which forcesappeared to affect the secondary lobules. In 1957Leopold and Gough gave a full account of centri-lobular emphysema, describing it as a frequentcomplication of the generalized form. Right ven-

tricular hypertrophy was present in only nine outof 65 cases of generalized emphysema, but was

seen in 41 out of 75 cases with added centrilobularemphysema.

Spain and Kaufman (1953) examined multiplesections of emphysematous lungs and describedchanges in bronchioles which they considered tobe the basic lesion of emphysema.Reid (1954, 1955, 1956) applied the serial section

technique to the study of lung nodules in chronicbronchitis and demonstrated obliteration or dila-tation of small bronchioles together with alveolarchanges. Bronchiolar changes were sometimeslocated in specimens by injecting the bronchi withradio-opaque material.McLean (1956a) used several methods to study

emphysema. He fixed some lungs by distendingthe air passages with formalin, and others by theintravenous injection of formalin into the cadaver.He examined part of his material by the Goughand Wentworth technique, but he also examinedand photographed lung slices. Emphysema was

classified into localized and generalized forms andthe latter was further subdivided into centrilobularand diffuse forms (see original article for fullclassification). Examples of these were photo-graphed under water with careful attention tolighting arrangements, and the photographs of thepresent article are similar to his, but show more

detail after barium sulphate impregnation. Inlater papers McLean (1956b, 1957a, b, and c)attributed the bronchiolectasis of centrilobularemphysema to a proximal bronchiolitis and air-trapping.

FIXATION METHODAll ordinary precautions were taken to avoid cut-

ting or tearing the lungs as they were removed. Ifadhesions were dense, extrapleural dissection was

carried out. Small cuts were sutured before fixation.The routine practice of running a pair of scissorsdown the membranous posterior wall of the tracheawas done with care, in order to preserve sufficientmain bronchus to take a cannula. Where delay was

inevitable, the lung was covered with a damp cloth toprevent the pleural surface from drying.The segmental bronchi were sucked clear of mucus

with a narrow glass cannula. A broad cannula was

then tied tightly into the main bronchus with string.

A rubber bung, with a circumferential groove,mounted broad end distally on glass tubing, wasfound ideal (Harrison, 1955) and a selection of varioussizes of these was kept available. If an importantspecimen had been cut near the first bronchialdivision, smaller cannulae were tied into the mainupper and lower lobe bronchi and supplied by aglass Y-piece.The lung was floated in water and distended gently

with 20% formol saline at a pressure of 10-12 in.(25-30 cm.) of fixative. When fully distended it wasimmersed in fixative and attached to the apparatus tobe described. If a segment failed to fill after severalminutes the pressure was briefly raised to 36 in.(90 cm.) until the obstruction was overcome.The usual practice with lungs which have been

treated in this way is to seal off the bronchus andallow the lung to float in formalin. I have examinednumerous specimens fixed in this way and have hadno difficulty in mapping out coarser grades of em-physema, e.g., as seen in Fig. 5, but with the finergrades of change errors may appear. The floatinglung flattens and shrinks as the formalin leaks awaythrough the pulmonary vessels. Formalin is a slowfixative and I have found that shrinkage can beprevented only by maintaining the pressure of theinjection at 10 to 12 in. for several days, preferablytwo weeks. There is no significant change in thevolume of the lung over the fixation period nor forweeks or months after the pressure has been released.The lung retains its anatomical features precisely andslices show even fixation.The main parts of the apparatus are illustrated in

Fig. 1. The head of pressure is supplied through asyphon from the flask D, the upper end of the over-flow H being set 10-12 in. (25-30 cm.) above the fluidlevel in the lung container F. Continuous suction isapplied at G, drawing fixative into the upper con-tainer A. When the level of fluid in the lung con-tainer drops below the lower end of the tube E, thevacuum breaks and fixative flows past the one-wayglass valve C into flask D. Excess fluid escapes intothe lung container by the overflow H, restoring thevacuum. The glass valve C prevents fixative frombeing drawn up from the flask D to the upper con-tainer A, and is made to carry a fast downward flowof fixative when the vacuum breaks. The clip B isadjusted to prevent the flask from overflowing.

Suction is applied in two ways. While the lung isfilling, a filter pump (Edwards's "speedivac" metalwater jet pump) is used to cope with the large volumeof fixative required. After 30 minutes this can bereplaced by an oil pump with an induction motor ofthe type used surgically to apply continuous suctionto pleural sacs, etc. (Roberts's suction pump). Thetime take for this slower pump to fill the upper con-tainer leads to a desirable intermittency and the cyclerecurs every two minutes approximately. Although asimple water pump would refill the reservoir effici-ently, there appears to be no pump available fordealing quietly with small volumes of fluid. Thepresent apparatus can be left to run without attention

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BRIAN E. HEARD

G

for several days at a time, and a vacuum pump of theabove type is subjected to far less wear and tear thanwould be suffered by a positive-pressure water pump.

The apparatus functions well with a filter pump andthe oil pump is necessary only if many lungs are tobe studied. Several lungs can be fixed at one timein a larger lung container, supplied in parallel fromthe flask D.The fixative chosen was 20% v/v aqueous

formalin; colour preservatives and buffers were

omitted. The strength of the formalin was higherthan usual to speed fixation and to allow for formalinvapour extracted by the vacuum.

Fixation under pressure was continued for as longas possible, usually one to two weeks. A minimumof three days was essential. Gough and Wentworth(1948) found enzymes to be active after prolongedformalin fixation, so the longest fixation periods pos-sible are recommended.

After long fixation the lung lies lower in the fixa-tive and may sink. At the moment, in an attempt toremove air bubbles, I am inflating the lungs withcarbon dioxide several times before distension withfixative (Tompsett, 1952).

BARIUM SULPHATE IMPREGNATION METHODThe fixed lung was sliced on a board fitted with

rails 0.8 cm. high to support each end of the 14 in.(35 cm.) blade of a ham knife (Cunningham andMiller, 1952). The lung was cut with the costalsurface lowermost and slices then ran antero-posteriorly and included the main segments. Severelyemphysematous lungs cut well if the pressure offormalin was maintained through the bronchi as theknife passed through the lung.Barium impregnation was devised to render the

translucent lung tissue opaque. A selected slicelateral to the main bronchi was squeezed lightly inwater and placed in a tray of warm, aqueous bariumnitrate (approximately 75 g. in 1 litre of water). Thelung was gently pressed in all parts to aid absorptionof the solution and, after one minute, the slice waslightly squeezed out and transferred to a warmaqueous solution of sodium sulphate (approximately100 g. in 1 litre of water). The reagents were storedin an incubator at 370 C. and were thus available foruse at any time. The lung slice was again pressed inall areas for one minute, squeezed out lightly andreturned to the barium nitrate. This was repeatedtwo to four times and the whitened slice was squeezedlightly in water and stored in a large vessel of 20%formalin. Lung slices became distorted permanentlyif they were not stored flat. The barium sulphateimpregnation usually increased the weight and causedthem to sink slowly in the fixative. Up to 12 slicescould be stored flat resting lightly one upon the otherwithout becoming distorted.Barium sulphate was precipitated very finely on all

structures and did not detach readily. The treatedslices were examined in trays under water. They weregreyish-white and no attempt was made to bring backthe original colour. Dust pigment was not obscuredby moderate barium sulphate impregnation, and sincecentrilobular emphysema affects the frequently pig-mented respiratory bronchioles, these showed up asdark holes against white unaffected lung-a great aidto visualization and to photography (with the slice inwater). The finer details, as viewed in water by meansof a dissecting microscope, were extremely satis-factory (see Fig. 4). The method has been used onslices of fresh tissue, fixed quickly by floating flat instrong formalin for one half to one hour, to demon-strate major findings urgently. It has also been usedon museum preparations of emphysematous lungs.

RESULTSLungs are being taken at necropsy from patients

with a history of chronic bronchitis and comparedwith a series from patients with non-respiratoryillnesses. From the study of this material to date,and in the light of recent work quoted in the intro-duction, the following anatomical classification ofemphysema has been framed: (1) Diffuse emphy-sema, and (2) centrilobular emphysema. Each ofthese may be (a) widespread or (b) localized.

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EMIPHYSEMA OF THE LUNGS WITH CHRONIC BRONCHITIS

FIG. 2.-Widespread diffuse emphysema (

The two main divisions rest on an appreciationof the lobular structure of the lung. In diffuseemphysema there may be changes in all parts ofthe secondary lobule, while in centrilobularemphysema the changes are mainly confined tothe middle parts. Frequently both varietiesoccurred in the same lung and were recordedseparately. The extent of the lesions wasindicated clearly by the terms widespread andlocalized.

a<#6+* W W I have not used the term; "generalized," because by

this McLean (1956a) de-i1; noted the extent of either

'11vdiffuse or centrilobularforms, while Leopold

WX~and Gough (1957) de-noted one form only

;'~ .:(diffuse). Further con-fusion arises when diffuseemphysema is localized,for if it were termed"generalized the localform would have to b_

L* called "localized general-X ized emphysema."

The above classificationneeds to be extended incertain instances. Manyroutine specimens fromelderly patients have

* * ,. bullae on the medial aspectof the upper lobe while therest of the lung shows verylittle change. This istermed " superficial em-physema" here. Occa-sionally the periphery of alobule is stretched fromthe septum (Fig. 13) and Ihave used the term para-

septal emphysema" forthis. A minor complica-

I W tion is that the layerof localized emphysemaaround scars may affectonly parts of lobules, butthis can be included in theterm "localized diffuseemphysema" for conveni-ence. Tension cysts(McLean, 1956a) can belabelled as such. " Senile "

1-4). emphysema can probablybe described as a mild

widespread diffuse emphysema of later life.Interstitial emphysema is outside the presentgrouping, as also are honeycomb and cystic lungs.Emphysematous cysts are recorded separately,though they may be part of a widespread emphy-sema. " Localized hypertrophic emphysema,"which occurs mainly in children (Silver, Kirklin,Harris, and McDonald, 1956), can be groupedanatomically as a form of localized diffuseemphysema.

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BRIAN E. HEARD

WIDESPREAD DIFFUSEEMPHYSEMA. - This isillustrated in Figs. 2-4.This is the left lung froma man of 55 who hadchronic bronchitis for 20years and died of cor pul- vmonale.* The left lowerlobe was partially col- X

lapsed and scarred froman attack of pneumoniaseven years before death.Not one normal secondarylobule was seen anywherein either lung. Fig. 2shows details of the upperlingular segment whichwas less affected than 4other segments. Mostlobules, even here, havelost the normal densedetail and are composedof large air spaces withfairly thick walls. This - Nchange often involves peri-pheral lobular tissue. TheV-shaped lobule in thecentre may appear at firstsight to be relatively nor-mal, but by the dissectingmicroscope it is seen to bemade up of soft, thin,atrophic walls of the typemore often seen in local-ized diffuse emphysema.The pulmonary arteries

were injected with a finebarium and gelatin mix-ture before fixation. In°Fig. 3 is an atrophic FIG. 3.-Extreme lobularlobule picked from theanterior apical segment. The appropriate branchof the pulmonary artery enters the lobule on theleft and, as a result of atrophy of the walls ofair spaces, can be followed to ramifications at pre-capillary level. In Fig. 4 the arteries are seen tobe almost the last remaining structures of thelobule apart from a few residual lightly pigmentedstrands of atrophic lung stretched across the inter-arterial gaps. A few capillaries are filled withinjected barium.The predominant change in this lung, however,

is the loss of fine alveolar structure and its replace-* " Cor pulmonale" is used to indicate combined cardiac andrespiratory failure, but the predominance of one or the other varies

from case to case.

4

atrophy in anterior apical segment of same lung as in Fig. 2 ( 3).

ment by relatively large, thick-walled spaces-awidespread diffuse emphysema of advanceddegree.CENTRILOBULAR EMPHYSEMA. This is a form

affecting more central respiratory bronchioles (abronchiolectasis). Fig. 5 shows these dilated bron-chioles lying in clusters well away from the inter-lobular septa. This lung was from a man of 51years who had chronic bronchitis for 10 years,following an attack of pneumonia. He died ofcor pulmonale (and Ellis' type II nephritis).

Fig. 6 shows part of the apical segment of theleft lower lobe of the lung of a man of 58 years

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FIG. 4.-Higher magnification of Fig. 3(x 10).

FIG. 5.-Widespread contrilobular emphy-sema ( x 3).

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FIG. 6.-Widespread centrilobular emphysema (mild) ( x 1-75).

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FIG. 7.-Widespread centrilobular emphysema ( x 2-2).

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FIG. 8.-Widespread centrilobular emphysema ( x 3).

who died of coronary thrombosis. He had " bron-chitis" at the age of 6 years, but complained onlylatterly of cough, worse in winter. He smoked 25cigarettes a day and stoked furnaces for over

20 years. The lung shows mild, but widespread,centrilobular emphysema. Almost every lobulehas a central cluster of slightly dilated, pigmentedbronchioles. The lesions were not detected in thefresh right lung at necropsy, but are obvious in thebarium-impregnated slices of the long-fixed lung.Control material shows that this is a true centri-lobular emphysema and not an artefact producedby distension with formalin. Note the relativelvnormal lung substance near the interlobular septa.

Fig. 7 is part of the anterior segment of theupper lobe of the right lung from a man of 75years who died of carcinoma of the left lung. Hesmoked 60 cigarettes a day from the age of 18,complained of a " smoker's cough " all his life, hadwinter bronchitis for " years," more serious for thelast five years, and three years before death hadhad bronchopneumonia. There is more marked

centrilobular emphysema than in the previous caseand the dilated respiratory bronchioles have runtogether to form prominent cyst-like spaces crossedby stretched vessels and remnants of bronchiolarwalls.

Fig. 8 is part of the lower lobe of the right lungfrom a man of 55 years who died of cor pul-monale. He had pneumonia 17 years previouslyand his chronic bronchitis dated from that event.There was post-inflammatory scarring of the upperlobe and widespread bronchiectasis. This sliceshows widespread centrilobular emphysema and,in spite of the absence of interlobular septa, thecentrilobular position of the lesions is shown bytheir tendency to surround the terminal branchesof the injected pulmonary arterial tree. For thesame reason, the lesions avoid the regions of thepulmonary veins.

Fig. 9 is the right lung of a woman of 37 whodied of cor pulmonale 13 years after a left-sidedthoracoplasty for pulmonary tuberculosis. For thelast four years she had chronic bronchitis with

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BRIAN E. HEARD

FIG. 9.-Widespread centrilobular emphysema with upper lobe accentuation ( x 0-63).

exacerbations in the winter. The lower lobe showsa mild grade of pigmented centrilobular emphy-sema in most areas. The middle lobe is almostnormal, though the absence of pigment may indi-cate previous inflammation (Gough, 1957). Theupper lobe shows advanced emphysema, heavilydust-pigmented. This is a case of mild wide-spread centrilobular emphysema with accentuationnear the scarring of healed apical tuberculosis.

Fig. 10 shows that the change in the upper lobe isbasically centrilobular in type (note the barium-gelatin injection of a number of the lobulararteries).Mixed patterns were common. Fig. 11 is the

left lung of a man of 68 years with a long historyof chronic bronchitis dating from gassing in thefirst world war. He died of cor pulmonale. In thecentre of the upper lobe there is marked centri-

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FIG. 10.-Higher magnification of upper lobe of Fig. 9 (x 1-9).

lobular emphysema which is becoming confluent inthe posterior apical segment, where rows of dilatedbronchioles (dark) are separated by bands of lessaffected lung (lighter) near septa and septal veins.The lighter areas are the only surviving foci ofrelatively normal lung. The details of the upperlobe are shown in Fig. 12. The bulla in the an-terior segment of the upper lobe may be either asuperficial exaggeration of centrilobular disease ora separate phenomenon, possibly best describedfor the present as superficial emphysema. In thelower lobe (Fig. 11) there are several types ofchange. There is centrilobular emphysema in themiddle zone. There is superficial emphysemaposteriorly. There is some fine feathery localizeddiffuse emphysema (not clearly visible in thephotograph) in the upper part of the posteriorbasal segment; it is similar to that in Fig. 14, andprobably a different or more marked variety ofpost-inflammatory change. In the lower part ofthe posterior basal segment there is post-inflamma-

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tory fibrosis with honeycombing. Much of theanterior basal segment shows diffuse emphysema.An uncommon mixed pattern is shown in

Fig. 13. It is from the right lung of a man of 76who had chronic bronchitis for a " few years," anddied of carcinoma of the oesophagus. There wascentrilobular emphysema of much of the upperlobe and of the upper parts of the middle andlower lobes. Two types of lesion can be seen inthe centre of the upper lobe (Fig. 13). In additionto centrilobular emphysema, the periphery of somelobules appears to have been stretched away fromthe thickened fibrous septa and associated septalveins, leaving thin filaments to bridge the gaps.A term which would seem to describe this appear-ance best is "paraseptal emphysema." Gough(1952) described bullae along blood vessels,bronchi, and septa. He attributed them to theexpanding force of respiration which seemed topull the degenerate lung substance from its frame-work.

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FIG. 13.-Centrilobular with paraseptal emphysema (x 2-15).

Centrilobular emphysema is probably the con-sequence o f centrilobular inflammation. If a

localized wedge of lung is inflamed, the conse-quence may be localized emphysema, as in Fig. 14.This is the anterior segment of the right upper lobeof a woman of 80 years who had no sign ofchronic bronchitis at any time, but had a febrilewinter illness two years before death. She died ofcarcinoma of the pancreas with metastases, andthe lung was taken as a control specimen. The

photograph shows two paler areas (betweenarrows) of characteristic localized diffuse emphy-sema associated with bronchiectasis. There aresome (dark) foci of localized centrilobular emphy-sema in the neighbourhood, but elsewhere the lungis normal.With recurrent attacks of pulmonary inflamma-

tion of this type a number of such localized areasmay accumulate, and may be associated withchronic bronchitis clinically. Such was the case

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BRIAN E. HEARD

FIG. 14.-Two foci of localized diffuse emphysema (between arrows). Bronchiectasis and localized centrilobular emphysema (dark) are alsopresent ( x 1-06).

illustrated in Fig. 15, which was from a man of75 who had had three attacks of pneumonia, 47,seven, and two years before dying from carcinomaof the prostate. He had had chronic bronchitisfor some years. The photograph shows scarringin several areas of the left lung (sometimes withbronchiectasis), and about each scar is a zone oflocalized centrilobular emphysema. The end-result is almost equivalent in extent to a wide-spread centrilobular emphysema.

In conclusion, the lungs of established chronicbronchitics very often show centrilobular emphy-sema (and occasionally diffuse emphysema). Thedegree and extent of emphysema in controlmaterial were minimal. Centrilobular emphysemawas usually widespread, but sometimes localizedareas or accentuations were seen about scarsfollowing pneumonia or tuberculosis. Some casesshowed bronchiectasis as well. The emphysema-tous lesions are revealed easily in specimens bythe methods described.

SUMMARYA series of lungs from patients with chronic

bronchitis is being collected and examined foremphysema. A number of the cases of well-established chronic bronchitis examined so farhave shown widespread centrilobular emphysema,while lungs of non-bronchitics showed, at most,very mild grades in occasional scattered lobules.Centrilobular emphysema has been missed until

recent years because it is difficult to see in col-lapsed lungs at necropsy. It is best studied informalin-distended lungs, but these distort ifallowed to float in fixative. A method is describedwhich overcomes shrinkage and distortion bymaintaining the intrabronchial pressure at 10 in.(25 cm.) of fixative for days or weeks at a time.The translucency of sliced lung tissue has been

overcome by barium sulphate impregnation. Theresulting opacity of the finest structures allowsreliable observations to be made by the naked eye

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v cm.

FIG. 15.-Localized centrilobular emphysema near many scars (x 0-5).

and fine details of air spaces can be studied by thedissecting microscope very satisfactorily. Someindication of this is given by the accompanyingillustrations. A classification is described.

I wish to thank Professor C. V. Harrison for hisinterest and advice. I also wish to thank Mr. J. G.Griffin for technical help, Mr. W. H. Brackenburyand Mr. I. T. Hinton for the photographs, and Mr.F. G. Saunders for drawing Fig. 1.

REFERENCESCunningham, G. J., and Miler, J. W. (1952). Thorax, 7, 170.Fletcher, C. M. (1952). Proc. roy. Soc. Med., 45, 577.Gough, J. (1940). J. Path. Bact., 51, 277.-(1952). Proc. roy. Soc. Med., 45, 576.

Gough, J. (1957). Personal communication.- and Wentworth, J. E. (1948). Proc. 9th int. Congr. industr. Mod.,

London, p. 661. Wright, Bristol.Harrison, C. V. (1955). Personal communication.Hoppleston, A. G. (1947). J. Path. Bact., 59, 453.Leopold, J. G., and Gough, J. (1957). Thorax, 12, 219.McLean, K. H. (1956a). Aust. Ann. Med., 5, 73.

(1956b). Ibid.,5, 254.(1957a). Ibid., 6, 29.

-(1957b). Ibid., 6, 124.(1957c). Ibid., 6, 203.

Oswald, N. C., Harold, J. T., and Martin, W. J. (1953). Lancet,2,639.

Reid, L. M. (1954). Ibid., 1, 275.-(1955). Thorax, 10, 199.

(1956). Proc. rov. Soc. Med., 4,771.Scadding, J. G. (1952). In Diseases of the Chest, Vol. I, p. 55, by

Marshall, Sir G., and Perry, K. M. A. Butterworth, London.Silver, A. W., Kirklin, J. W., Harris, L. E., and McDonald, J. R.

(1956). Dis. Chest, 30, 456.Spain, D. M., and Kaufman, G. (1953). Amer. Rev. Tuberc., 68, 24.Tompsett, D. H. (1952). Thorax, 7, 78.

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