parenchymal, bronchiolar, and bronchial measurements in ...the end of the small airways. in...

Thorax (1970), 25, 556.

Parenchymal, bronchiolar, and bronchialmeasurements in centrilobular emphysema

Relation to weight of right ventricleJ. BIGNON, J. ANDRE-BOUGARAN, and G. BROUET

Clinique Pneumologique, H6pital Laennec-75, and Institut National de la Sante et de laRecherche Medicale, Paris

Measurements of lung parenchyma, membranous bronchioles, and bronchial mucous glandhyperplasia were made on lungs from eight cases of pure centrilobular emphysema (CLE) and on

five normal lungs. The lungs were fixed in formalin and inflated under partial vacuum at a

standard transpulmonary pressure of +30 cm. H20. The results obtained from the upper halvesand the lower halves of the lungs were compared. The circulatory effects of the disease were

measured by weighing the heart ventricles, by studying the small pulmonary arteries in micro-scopical sections, and by post-mortem arteriography. Whereas the parenchymal and internalsurface areas destroyed by the emphysematous spaces were relatively moderate and localized,right ventricular hypertrophy was noted in most of the cases. In these cases bronchiolar stenoseswere found scattered throughout the whole lung and there was a reduction in the number ofthese bronchioles, mainly in the upper halves of the lungs. In CLE ventilatory disturbances were

caused not only by the centriacinar dilated spaces delaying gas diffusion, but also by scatteredbronchiolar stenoses situated at the termination of the conducting air passages. The stenosesseemed the more important cause. It was shown statistically that chronic arterial pulmonaryhypertension and right ventricular hypertrophy were mainly the result of functional disturbances,especially hypoxia and abnormalities of VA/Q produced by the two structural changes situated atthe end of the small airways.

In centrilobular emphysema, parenchymal destruc-tion is situated at the level of the respiratorybronchioles, producing initially enlarged centri-acinar air spaces but leaving more or less intactalveoli distal to these spaces (Reid, 1967). Thecentriacinar holes may join to form larger centri-lobular spaces (Leopold and Gough, 1957). Thistype of emphysema is usually associated withchronic bronchitis and is thought to result fromrespiratory bronchiolitis. During its course, andoften at an early stage, it usually results in severerespiratory failure with right ventricular hyper-trophy (Leopold and Gough, 1957; Dunnill,1965; Hicken, Heath, and Brewer, 1966b; Wyattand Ishikawa, 1968; Bignon, Khoury, Even,Andre, and Brouet, 1969).

The ventilatory disturbances produced by centri-lobular emphysema have been shown by the useof a model to be almost exclusively caused byan increased diffusion time of gas moleculesthrough distended centriacinar or centrilobularspaces before they reach the respiratory exchange

area of the lung (Staub, 1965; Gomez, 1965;Cumming, Horsfield, Jones, and Muir, 1968).However, such a model hardly accounts for theseverity of most of the changes observed in casesof centrilobular emphysema. Usually only theupper zones of the lung and less than 40% ofthe parenchymal volume show centriacinar spaces(Snider, Brody, and Doctor, 1962; Thurlbeck,1963), and it is uncertain whether, in addition tothe centriacinar spaces, some other obstacle toalveolar ventilation may be present throughoutthe lung. Such an obstacle might be caused bybronchiolar narrowings which were described byMcLean (1958). Previously we have shown, usinga quantitative method, that widespread bronchiolarstenoses were present in chronic obstructivebronchopulmonary disease with or without emphy-sema (Bignon, Khoury, Even, Andre, and Brouet,1968, 1969). Recently it has been emphasized thatin chronic obstructive pulmonary disease theobstruction to airflow is situated in small bronchiof less than 2 mm. diameter (Hogg, Macklem, andThurlbeck, 1968).

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Parenchymal, bronchiolar, and bronchial measurements in centrilobular emphysema

The present study, employing morphometricmethods, was designed to investigate the quantita-tive relationship between the alveolar (lung paren-chymal) and bronchiolar damage in centrilobularemphysema, and the severity of the resultingchronic pulmonary hypertension and right ventric-ular hypertrophy. The importance of permanentstructural changes in the pulmonary arteries asa cause of the pulmonary hypertension was alsoinvestigated.

MATERIAL AND METHODS

Eight cases of pure centrilobular emphysema (CLE)were studied. Post-mortem examinations were carriedout according to a method described previously(Bignon et al., 1968). The lungs were fixed by endo-bronchial formalin infusion and expanded by a partialvacuum of -30 cm. H20 for 72 hours. The lungvolume was measured after fixation by weighing thevolume of water it displaced. The lungs were thensliced into five or six sagittal macrosections with athickness of 1 cm., and the appearances of CLE weresimilar to those described by Leopold and Gough(Fig. 1). The proportion of the total lung parenchymamade up by the centrilobular spaces was evaluatedby submerging the slices of lung in water and usinga stereomicroscope combined with the point-countingmethod (Dunnill, 1962). The proportion of the lungtissue volume due to CLE was calculated for theupper half, the lower half, and the whole lungseparately.Twenty standardized blocks of lung tissue (10 from

the upper half and 10 from the lower half of onelung), and taken from each lung, were sampled by astratified randomized technique. These blocks,measuring about 20 x 30 mm., were then processed inthe usual way and embedded in paraffin undervacuum. Sections, 5 , thick, were stained with haem-atoxylin and eosin and by Weigert/van Gieson forelastic fibres. The mean linear shrinkage (p) for pro-cessing was determined in each case by measuringthe length (L) and breadth (1) of fixed blocks (1) andprocessed slides (2) on the 20 randomized samplescalculated from the formula (Weibel, 1963)

P%/L2x 12 (1)

Alveolar internal surface area (ISA) was deter-mined by the mean linear intercept method of Camp-bell and Tomkeieff (1952) using Weibel's multipurposetest system (Weibel, Kistler, and Scherle, 1966)inserted into the head of a Leitz microscope (magni-fication x50). The number of intercepts in each fieldwere card-punched and the variance was calculatedfor the upper half, the lower half, and the wholelung as follows:

1yi2 2

Var (y)-= ny -y (2)(n- 1)

where Var (Y) = variance of the mean obtainedby two-stage sampling (sections and fields), n -number of sections, yi = mean for sections andy = mean for all microscopical fields. Then, c and

relative error in per cent 100 x - were calculated.

The processed mean linear intercept (Lm') wasdetermined according to

LTNi (3)

where LT = total length of the test system lines forall fields studied, and Ni = total number of timesthat the lines intersect alveolar walls. The result wasexpressed in microns. The fixed mean linear intercept(Lm) was obtained by:

Lm=Lm' x p (4)Lm was corrected to the radiographic lung volume(VLR.) or to the predicted lung volume (VL pred)according to the formula (Thurlbeck, 1967b)

Lmc=Lmx (Vlor)IR. 1/3 (5)

The internal surface area at a transpulmonary pres-sure of 30 cm. of formalin was obtained in squaremetres using the formula:

4 X VF X XISA= Lm (6)

where VF = fixed lung volume and X = fraction oflung volume occupied by parenchyma. The ISA hasbeen expressed at a standard lung volume of 5 litres(ISA5), according to Thurlbeck (1967a, b), and at thepredicted lung volume (ISAc pred.), or at themeasured total radiographic lung volume (ISAcax) aspreviously described by Bignon et al. (1969).Morphometry of membranous bronchioles (non-

respiratory and non-cartilaginous) was carried outusing the method described by Bignon et al. (1969).Instead of micrometric measurement of bronchiolarinternal diameters (ID), the bronchioles were countedin nine groups. The internal diameters of thebronchioles were chosen according to dataobtained by Horsfield and Cumming in anormal bronchiolar tree (Horsfield and Cumming,1968) and ranged from group 0, less than 100 pu;group 1, 101 , to 200 ,u; group 2, 201 to 350 ,;group 3, 351 to 500 ,; group 4, 501 to 700 ,i;group 5, 701 to 900 ,u; group 6, 901 to 1,200 ju;group 7, 1,201 to 1,700 ,IL; to group 8, over 1,700 ti.The scale used was inserted into a x 12-5 projectorhead and was made up of eight concentric circles,the distance between the circles representing theranges of diameters described above. Using a x 4objective, the linear fixed dimensions were measureddirectly, the diameter of each circle being correctedby an arbitrary shrinkage coefficient (f = 0-77). Aninternal diameter of 350 ja was chosen as the lowerlimit for internal diameters of normal membranous

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Parenchymal, bronchiolar, and bronchial measurements in centrilobular emphysema 559

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J. Bignon, J. Andre-Bougaran, and G. Brouer

bronchioles. In five normal adult subjects the per-centage of bronchioles less than 350 ,u diameter wasfrom 8 to 18-5% (mean 13 3%0).The bronchiolar density per square centimetre of

fixed lung was calculated by counting all bronchiolartransections, either circular, oblique or longitudinal.Counting was carried out on the whole area of themicroscopical sections. Bronchiolar transections inter-cepted by the right and upper border lines weredismissed. The number of bronchioles was calculatedper square centimetre of fixed lung (Thurlbeck, 1969),the surface of each block having been determined byaccurate measurement of length and breadth underwater. The number of bronchioles per square centi-metre of fixed lung (Nb/cm2 F) was corrected to theradiographic or predicted lung volumes, using theformula:

Nb/cm2 c=Nb/cm2 Fx (VL VF d)2/3 (7)

These measurements (ID and Nb/cm2) were carriedout separately for the upper half and the lower halfof each lung.The bronchi were studied grossly and microscopi-

cally. Mucous gland hyperplasia was estimated bytwo methods: (1) measurement of the Reid index(Reid. 1960, 1967) (ratio of bronchial gland thicknessto wall thickness) and (2) measurement of the volumeof the mucous glands situated inside the bronchialwall to the total volume of the bronchial wall usingthe point-counting procedure (Hale, Olsen, andMickey, 1968; Dunnill, Massarella, and Anderson.1969), using Weibel's test-system with 42 points(Weibel et al., 1966). The result was expressed as apercentage. This measurement was carried out at amagnification of x 50 using an automatic stage ona section of the whole bronchial wall extending fromthe peribronchial connective tissue to the lumen. Bothmeasurements were carried out on five bronchialtransverse sections 5 it thick (1 principal bronchus, 2upper and lower lobar bronchi, and 2 segmentalbronchi). The results were the mean data obtainedon five bronchi.

Elastic and muscular pulmonary arteries as wellas pulmonary arterioles were studied qualitativelyboth in microscopical sections and by postmortemarteriography. Arteriograms were carried out by amethod described previously by Schlesinger (1957).The left and right ventricles were carefully dis-

sected free from fat and weighed separately accord-ing to the method described by Fulton. Hutchinson,and Jones (1952). A right ventricular weight less than65 g. and a Fulton's ratio higher than 2-2 wereregarded as normal. The extent of the right ventricularhypertrophy (RVH) was regarded as an indication ofthe severity of the chronic pulmonary arterial hyper-tension (PAH) (Hicken, Heath, Brewer, and Whitaker,1965).

Statistical analysis was carried out by the paired't' test and by the relationship coefficient.

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FIG. 2. Internal surface area corrected to a standardvolume of 5 litres (ISA5) has been plotted on a diagramfrom 8 patients with CLE, 5 normal subjects, and 3patients with PLE grade III involving more than 60 percent ofparenchyma, with no or moderate right ventricularhypertrophy. The smooth curve represents mean normalvalues from cases reported elsewhere (Weibel, 1963;Dunnill, 1962; Duguid et a]., 1964; Hicken et al., 1966a;Thurlbeck, 1967b). * CLE; A PLE>600%

RESULTS

Table I shows the quantitative anatomical findingsfor lung parenchyma, membranous bronchioles,bronchi, and right ventricular weights.

LUNG PARENCHYMA Macroscopic and microscopicstudies showed that emphysematous destructionoccurred predominantly in the upper half of thelung. Thus, the volumetric proportion of CLEevaluated in macrosections was, in every case,significantly (P<000l) greater in the upper half(mean=38-7%) than in the lower half (mean=16%) of the lung. Likewise, the mean linear inter-cept (Lm and Lmc) was significantly (P<0-001)larger in the upper half (mean= 569 ,u) than in thelower half (mean =448 ,u). Such parenchymaldestruction was, however, relatively limited. Thusin seven out of the eight cases the internal surfacearea, expressed at a 5 litres standard lung volume(ISA5), was moderately decreased compared withthe theoretical values in cases without emphysema.It was not, however, reduced as much as in casesof severe panlobular emphysema (Fig. 2). Further-

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ISA5(i2)I50 -

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r=-0948p< 0001

0 y=-0446x+53263

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FIG. 3. Diagram showing a high degree of correlationbetween macroscopic volumetric proportion of CLE andISA5 measured microscopically on randomized sections.

TABLE IICOMPUTED CORRELATION COEFFICIENTS FOR SOME

VARIABLES

8 CLE Cases 13 (CLE+Control)Relationship Cases

r p r P

°/0 CLE and Lmc (UH) 0-796 < 0-02 0-917 < 0-0015% CLE and Lmc (LH) 0-870 < 0-01 0-877 < 0-001°/ CLE and Lmc (W) 0 930 < 0-001 0-961 < 0-001°/° CLE and ISA5 -0-948 <0-001° CLE and Nb F (UH) -0-800 < 0-02% CLE and Nb F (LH) -0-576 > 0-05°/ CLE and Nb F (W) -0 569 > 0-05° CLE and Nb C (UH) -0540 > 0-05° CLE and Nb C (LH) -0-610 > 0-05% CLE and Nb C (W) -0-358 > 0-05Lm and Nb F (UH) -0556 > 0-05 -0-830 < 0-001Lm and Nb F (LH) -0-411 > 0-05 -0-488 > 0-05Lm and Nb F (W) -0-456 > 0 05 -0 744 < 0-01Lmc and Nb C (UH) -0-410 > 0-05 -0 793 < 0-01Lmc and Nb C (LH) -0-244 > 0-05 -0-398 > 0-05Lmc and Nb C (W) -0-212 > 0-05 -0-653 < 0-02°/0 bronchial mucousglands and Reid index 0-891 < 0-001

° CLE and RVW 0 758 < 0-05% CLE and Fulton ratio* -0-690 > 0-05ISA, and RVW -0-654 > 0 05ISA5 and Fulton ratio0 -0 740 > 0 05°/ br < 350 p and RVW 0-857 p < 0-01/° br < 350 i andFulton ratio* -0-925 p < 0-01

%/ CLE+ / br < 3501and VD 0-859 P < 0-01

'/,CLE+ Y. br < 35011and Fulton ratio* -0859 p < 0-02% CLE and% br < 350 z (UH) 0-665 p > 0-05

°/0 CLE and% br <350y (LH) 0-717 p<0-05

°/0 CLE and°/ br < 35011(W) 0-714 p < 0-05

/0 CLE and RVW(/0 br < 350 z beingconstant) 0-408 p > 0-05

%/ br < 350 i andRVW (Y. CLE beingconstant) 0-692 p > 0 05

* Case 7 was excluded because of a left ventricular hypertrophyKey: see Table I

more, it appeared that the mean linear interceptmethod carried out on a limited number of ran-domized microscopic samples gave as good anindication of parenchymal destruction as themacroscopic quantitative study. This was shownby the good correlation which existed between themacroscopic volumetric proportion of emphysemaon one side and, on the other side, ISA5 (Fig. 3),the mean linear intercept for an upper half, lowerhalf, and total lung (Table II).

MEMBRANOUS BRONCHIOLES In seven cases, asshown by bronchiolar histograms, the percentageof membranous bronchioles with internal dia-meters less than 350 it was increased (range 33 to66% for the whole lung). In case 1, in whom theresults were nearly normal, CLE and chronicbronchitis were mild and there was little airwaysobstruction (FEV1= 2,345 ml., i.e., 75% of theo-retical values, and FEV1 /VC= 58%), only slightright ventricular hypertrophy, and no respiratoryfailure.

In these seven cases, the stenoses in the mem-branous bronchioles were scattered throughout thelung with slightly more in the lower halves thanin the upper halves (P<0-05) (mean percentage ofmembranous bronchioles with internal diametersless than 350 ,l were 39-7% for the upper halvesand 47-8 % for the lower halves) (Fig. 4). The

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FIG. 4. Bronchiolar histogram in a patient with CLEcompared with a normal subject (ranges of internaldiameter groups are given in the text).

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FIG. 5 (c)FIG. 5. Different histological patterns of narrowed membranous bronchioles inCLE: (a) bronchiolar stenosis with inflammatory changes in the wall; (b) narrowedbronchiole with an infolded mucosa; (c) mucopurulent plugs in bronchiolar lumen(H. and E. x 45).

narrowings were due to bronchiolar wall lesions,often severe, and were accompanied by inflam-matory cellular infiltration and fibrosis. Mucus ormuco-purulent plugs obstructing the bronchiolarlumens were observed in some cases, and in case6 bronchiolar contraction had caused infolding ofthe wall (Fig. 5). The bronchiolar density persquare centimetre was much less in the upperhalves (mean: Nb/cm2 C=039) than in the lowerhalves (mean: Nb/cm2 C=053) (P<0-02) of thelung. This difference was not observed in fournormal lungs. In the present series of CLE cases,the bronchiolar density appeared to be reduced asthe extent of the parenchymal destruction in-creased, as shown by the correlation existing inTable II. This was probably a consequence ofdestruction of some of the bronchioles situatedin the zones of CLE.

BRONCHI The mucous gland hyperplasia wasdemonstrated by two different quantitativemethods which gave similar results (Table II).Whereas clinical chronic bronchitis was found inall cases, mucous gland hyperplasia was foundonly in seven. No other important changes orlocalized bronchiectasis were detectable.

PULMONARY ARTERIES In cases 1, 3, 4, 5, and 7 noqualitative alteration of the muscular pulmonaryarteries (with external diameters ranging from1 to 01 mm.) or pulmonary arterioles (with

2S

external diameter less than 01 mm.) was detected.In cases 2 and 6, however, intimal fibrous thicken-ing reduced the lumen of the pulmonary arteries.Many thrombi were noticed in branches of thepulmonary arteries, some of them having under-gone organization. The heaviest right ventricleswere found in these two cases. The appearance ofthe pulmonary arterioles in case 6 is shown inFig. 6 and is compared with those observed incase 3 in which there was much less right ven-tricular hypertrophy. Cardiac catheterizationshowed that in case 3 the mean pulmonary arterypressure was 42 mm. Hg, and the calculated pul-monary arterial resistance was 450 dynes/sec./cm.r5, whereas in case 6 the mean pulmonaryartery pressure was 60 mm. Hg, and the calculatedpulmonary arterial resistance was 1,140 dynes/sec./cm.-5. Bronchopulmonary arterial anasto-moses were not found in any of the cases.

RELATION BETWEEN STRUCTURAL AND QUANTITATIVELUNG DATA AND WEIGHT OF RIGHT VENTRICLE Asignificant correlation was found between themacroscopic volumetric proportion of CLE andthe right ventricular weight. Likewise, ISA5 cor-related with right ventricular weight. The rightventricular weight, or Fulton's ratio, correlatedclosely with the percentage of bronchioles of lessthan 350 u in diameter. The addition of both per-centages (i.e., percentage of emphysema and per-centage of bronchioles of less than 350 ,u diameter)

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FIG. 6. Small pulmonary arteries (flled with barium gelatine injection mass) with external diam-eters of about 1O00p. (a) Case 6 (RVW= 220 g.). Pulmonary arteriole with a single elastic lamina.Fibrous intimal thickening was noted in most arteries of this size, as shown here ( x 420). (b) Case 3(RVW= 135 g.). Small pulmonary artery showing a distinct coat of circular muscle and an elastictissue hyperplasia ( x 420).



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FIG. 7. Correlations between right ventricular weights(x-axis) and peicentages (y-axis) of centrilobular emphy-sema or of bronchioles with internal diameter less than350 I. Correlation with addition ofboth percentages withright ventricular weight is shown by the dotted upper line.

correlated well with the right ventricular weightor Fulton's ratio (Fig. 7). As both these percent-ages showed a correlation, partial correlations werecalculated with the right ventricular weight. Thecoefficient r was higher (0-692) between RVW andpercentage of bronchioles of <350 ,u (the percent-age of CLE being constant) than between RVWand percentage of CLE (0-408) when the percent-age of bronchioles of <350 ,u was constant.

DISCUSSION

MECHANISM OF VENTILATORY DISTURBANCES IN

CENTRILOBULAR EMPHYSEMA Ventilatory distur b-ances in CLE cannot be accounted for only bydecrease of internal surface area. Indeed, in themajority of the cases studied the intact paren-chyma accounted for 50 to 77% of the volume ofthe lungs and the internal alveolar surface area

was only slightly reduced. These results, as

previously stressed by Dunnill (1965), are thereverse of the findings in severe PLE cases in whichthere is frequently minimal respiratory failure andright ventricular hypertrophy, although emphy-sema may destroy as much as 80% of the lungparenchyma, thus seriously reducing the internalventilatory surface area. Staub (1965) and Gomez(1965) emphasized that the ventilatory disturb-ances in CLE were mostly due to the enlargedcentriacinar spaces, which were situated in astrategic position between the conductive zoneand the respiratory exchange area, and sloweddown gas diffusion. As a result, Dunnill (1965)

pointed out that the number and the distributionof these abnormal air spaces were a more reliableguide than their size and the total lung volumeinvolved. However, the predominant location ofthe centrilobular foci in the upper half of the lung,demonstrated here as well as by Snider et al.(1962) and Thurlbeck (1963), suggests that thistheory cannot account for all the facts. Indeed,more than half of the lung parenchyma and par-ticularly the lower halves of the lungs, which arethe best perfused and ventilated (West, 1965),generally show much less centrilobular emphy-sema. This suggests that other mechanisms areresponsible, especially increase of terminal airwaysresistance. Leopold and Gough (1957) noticedinflammatory narrowings in 12% of the respiratorybronchioles supplying CLE spaces, and narrowingof membranous bronchioles was not reported bythem. The present morphometric study of themembranous bronchioles showed that bronchiolarnarrowings were scattered randomly inside thelung, including zones without emphysema. More-over, the degree of these bronchiolar narrowingsseemed related to the severity of chronic respi-ratory failure. These inflammatory stenoses situ-ated at the end of the conductive air passagescould play an important part in ventilatory distur-bances, as discussed in a previous paper (Bignonet al., 1969), and were demonstrated in recentphysiological studies by Hogg et al. (1968).

MECHANISMS OF CHRONIC PULMONARY ARTERIALHYPERTENSION AND RIGHT VENTRICULAR HYPER-TROPHY IN CLE Right ventricular hypertrophywas noted in 55% of the 75 cases studied by Leo-pold and Gough, and the majority of authors havenoticed the frequency of RVH in CLE (Dunnill,1965; Hicken et al., 1966b; Bignon et al., 1968;Wyatt and Ishikawa, 1968) even in cases withmoderate emphysema and sometimes at an earlystage. Nevertheless, the cause of the PAH or RVHis often uncertain or controversial.Permanent structural changes in the pulmonary

arterial system are a matter of debate, and evenif pulmonary arterial destruction occurs, it is ofminor importance as a cause of chronic cor pul-monale in CLE, because in some cases RVHdevelops with only moderate parenchymal destruc-tion (Hicken et al., 1966b). Compression of thepulmonary arterioles by the centrilobular air-distended spaces, which was suggested by Dunnill(1961) as a cause of pulmonary hypertension, wasnot found in this study. Heath (1968) showed thatthe small pulmonary arterial vessels oftenpresented characteristic histological features in

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J. Bignon, J. Andre-Bougaran, and G. Brouet

emphysema when there was associated right ven-tricular hypertrophy. These changes includeddevelopment of longitudinal muscle in the intimaof pulmonary arterioles, the development ofmedial circular muscle in the pulmonaryarterioles, and a lack of hypertrophy of the medialmuscle in the large muscular pulmonary arteries.This triad of structural changes might account forthe increased pulmonary vascular resistances inCLE. Such vascular changes, however, are notonly characteristic of emphysema but are foundin all conditions of chronic hypoxia (Naeye, 1962).The potentially reversible nature of these arterialchanges is probably related to the reversibility ofpulmonary arterial hypertension following reliefof chronic hypoxia (Pefialoza, Sime, Banchero,and Gamboa, 1962; Vogel, Cameron, andJamieson, 1966; Abraham, Cole, and Bishop,1968).In six cases of the present series there were no

major structural changes in the muscular pul-monary arteries and pulmonary arterioles. Thepulmonary arterial vessels, however, were not sub-jected to quantitative studies, as proposed by Arias-Stella and Saldafia (1962), Naeye (1962) or Hickenet al. (1965). Thus detection of mural changesin distal precapillary arterioles, similar to thoseobserved in healthy subjects living at a high alti-tude, in kyphoscoliosis (Naeye, 1961) or in thePickwickian syndrome may have been missed.Only in two cases were permanent and irreversiblevascular changes found to explain the extent ofRVH, and these consisted of intimal fibrous

FIG. 8. Structural model designed to show the site ofventilatory obstacles in CLE.

thickening causing narrowing of the arterioles and,to a lesser extent, of the muscular arteries. Thesechanges most probably resulted from organizedscattered thrombo-emboli. Thus pulmonarythrombo-emboli, which are frequently found inchronic bronchopulmonary disease (Dunnill,1961; Ryan, 1963; Bignon et al., 1969), may helpto increase the pulmonary hypertension in somecases.

In our cases, RVH and, in consequence, PAHappeared to be related to the quantitative struc-tural damage to the lung parenchyma and bron-chioles. Of these changes, bronchiolar stenosesplayed the more important part and its importance,even when minimal emphysema is present, hasbeen stressed previously (Esterly and Heard,1965; Bignon et al., 1969). It is questionable, how-ever, whether the high pressures generated beyondbronchiolar narrowings during coughing coulddisrupt respiratory bronchioles, as suggested byMcLean (1958). This would not account for thelocalization of centriacinar holes in the lungs.Pulmonary hypertension appears to result fromfunctional factors, especially hypoxia, caused bystructural changes in the airways. Thus, a newstructural model can be constructed to account forventilatory obstacles in CLE (Fig. 8). In the upperhalf of both lungs there are two obstacles 'inseries', first, bronchiolar narrowing in the conduc-tion zone and, second, centriacinar dilated airspaces in the intermediate zone. In the lowerhalves of the lungs there is mainly bronchiolarnarrowing before the zone of diffusion. Thus,these two obstacles interfere with the transfer ofrespiratory gases in a zone where good gas con-duction and diffusion are most needed (Gomez,1965). Because the centriacinar branches of thepulmonary artery generally remain intact, there isgood vascular perfusion but little or no ventilationat the level of the peripheral alveolar exchangezone. Therefore, in CLE a significant ventilation/perfusion abnormality occurs throughout the lung,even though parenchymal destruction is moderateand localized to its upper portion. Pulmonaryarterial hypertension and the resulting right ven-tricular hypertrophy are a sequel to musculariza-tion of the pulmonary arterioles caused byhypoxia (Heath, 1968), but in some cases thesechanges in the pulmonary vessels are increased bywidespread organized thrombotic emboli.

The authors wish to thank MM. P. Even, B.Ducimetiere (Unit6 de Recherche Statistique) and Ch.Berthet (Ecole Normale Superieure) for helpful adviceand collaboration, and Miss Huckendubler, Mrs.Laval and M. Bargy for technical assistance.

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This work was supported by a grant from theD,16gation G6n6rale A la Recherche Scientifique etTechnique (D.G.R.S.T.).

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