Pathogenesis of Emphysema: Experimental Observations*

Pathogenesis of Emphysema: Experimental Observations* ROBERT

G.

ROSSING, M.D. AND JAMES

R. CLAY,

MAJOR, USAF, MC··

Brooks Air Force Base, Texas

M

physema, in their opinion, is not associated with bronchiolitis, but may be a result of inspiratory fixation. Richards' and Krahl' also suggest that emphysema originates in disturbance of the most peripheral radicals of the bronchial tree. In the views of each of these investigators, except Heppleston and Leopold, bronchiolar obstruction is an early feature of the pathogenesis and alveolar disruption results from air trapping possibly abetted by inflammatory weakening of alveolar walls and sudden pressure imbalances such as may arise during coughing. Strawbridge-· I ' and Boren,1I on the other hand, place the initial lesion in the alveolar wall and view emphysema as a form of tissue atrophy which is caused either by vas.cular or inflammatory changes. Ebert and Pierce' have focused their attention on the connective tissue skeleton and the adverse effects on it of continuous stress. In these schemes, tissue alteration and destruction are primary and airway obstruction results from loss of tractional support of the nonrigid bronchioles.

ANY FACTORS HAVE BEEN SUGGESTED

as playing a role in the pathogenesis of emphysema/ each supported by evidence either from careful observation, from experiment or from soundly based theory. It is probable that several of them, perhaps indeed. all of them, are valid and the problem becomes one of synthesizing from them the most likely pathogenetic scheme. The schemes proposed to date may loosely be classified into two groups, those which would place the primary lesion in or immediately adjacent to the airways (bronchioles) and those which would place it in the periphery of the lobules (alveolar walls, capillaries, connective tissue). Stated in another way, the controversy is between those who regard airway obstruction as primary and those who regard tis.c;ue damage ac; the initial event with airway obstruction as a result. Spain and Kaufman' and McLean' have stressed the changes in the bronchioles and have suggested that the rest of the picture of emphysema may be secondary to obstruction at this level. Liebow41 and Anderson, et al! have alc;o emphasized the importance of bronchiolitis, but feel that, in addition, interstitial inflammation of the surrounding alveolar walls is necessary to produce the destructive changes which are so prominent in advanced emphysema. Heppleston and Leopold' agree that bronchiolitis is a conc;tant feature of centrilobular emphysema, but regard the development of emphysema as a purely destructive process since significant bronchiolar occlusion is rarely demonstrable. Vesicular em-

EFFECTS OF CHRONIC EXPOSURE TO PHOSGENE IN THE Doc Because of the evidence, physiologic and pathologic, which implicated bronchiolitis as a factor in the development of emphysema, it seemed worthwhile to try to produce chronic bronchiolitis in an experimental animal and to studv the late effects of such a process. For ~asons discWRd more in detail elsewhere/ ' ·I • phosgene (carbonyl chloride, COCl:!) was chosen as a logical agent. Briefly summarized, the reasons were these. (a) Necropsies of casualties from the use of phosgene as a war gas and animal experiments on its toxicity had confinned the fact that it produced its major damage in the bronchioles.

·From the Departments of Internal Medicine and Pathology, USAF School of Aerospace Medicine. Aerospace Medical Division (AFSC). ··Present address: Athens General Hospital. Athens, Ga. The animal experiments described herein were conducted according to the "Principles of Laboratory Animal Case" of the National Society for Medical Research.

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1 (upper): :-Jonnal dog lung (X23). Terminal bronchiole d i v i din g into two respiratory bmnchioles. :-Jote regularity of pall ern of lung parenchyma with alveoli of unifonn size. Alveolar duclS may also be identifif'd. FIGlIRE 2 (center): Area of pulmonary edema from lung of a dog which died a few houn after second exposurt> to phosgene (X!:!). !\;ote also small arf'as of inflammatory reaction and hemorrhage. FIGI'RE:I (lower): A cut e bronchiolitis and peribronchiolitis in lung of a dog sacrificed 48 hours after a single exposure to phosgene (X23). !\;ote extf'nsivl' hl'lllOrrhage around most severely involved bronchinlt>. Slight airspace o\"t>rdistension is shown in onl' area. FIGl"RE

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: b) Followup studies on survivors of ~as attacks and of \'ictims of accidental industrial exposure suggested that. in the human, such exposure could produce an increased incidence of chronic lung disease. especially of chronic bronchitis and emphysema. Twenty-th'e mon~1 dogs were exposed to phosgene in concentrations varying between 25 and 40 parts per million for 30 minutes three times a week. Studies of respiratory mechanics (in 14 animals) and of the distribution of inspired air (in nine animals) were carried out before the experiment and at inten'als during and after exposure. Detail.. of the methods emploved and of the results have been reported...·'· Beginning in the first week of exposure there was a sharp rise in the dynamic elastance, that is. the lun~ resisted distention and required up to eight times more pressure to produce an equal static volume change. Resistance to air Row in the lower aif\\'ays also increased. but the dominant change during the first three weeks was that in the elastic behavior. At this time, the animals were frequent Iv markedly tachypneic. appeared acutely dyspneic and, at times. cyanotic. Deaths from acute respiraton' insufficiency were common and both accidental casualties and animals sacrificed for pathologic stud\' showed a t\'pical histologic picture. There were extensive areas of pulmonary edema (Fig. 2) alternating with areas of apparent normal aeration. Tenninal and respiratory bronchioles were severely damaged and there was frequently iO"olvcmcnt of the surrounding lung with inRammatory infiltrate and hemorrhage (Fig. 3). Many bronchioles appeared completeI\' occluded by inRammatory exudate. Scattered areas of alveolar o\'erdistension were seen, but no e\'idence of alveolar wall breakdown was noted. .,\fter the third week. studies of respiratory mechanics showed most prominently a picture of increasing obstmction to airRow. Elastance remained somewhat elevated. but the breathing pattern revealed active expiratory effort. prolongation of the

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FICl:RE 4 (upper): Acute bronchiolitis still present in a dog sacrificed 24 hours after 19th exposur.:' tn phosgene ov.. r a period of six we.. ks (X23), Sote again involvemt'nt of adjacent lung par.:'nchyma. FICt'RE 5 (center): Chronic alveolitis in the lung of a dog sacrificed ont' week after 20th exposun' to phosgent' (X39), ~ot .. thick..ning and apparent shortening of alveolar septa.. and infiltration with inflammatory cells, FICI'RE 6 (Jow..r): Two adjacent respiratory bronchioles partially occluded hy organizing inflammatory tissue (X:19), From a dog sacrificed two weeks after 20th t'xposure to phosgt'ne.

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expiratory phase and a return to nonnal respiratory frequency, such as are characteristic of obstructive airway dL.:;ease in the human. .-\1 the same time, nitrogen washout studies revealed progres.'iive disturbance of the unifonnity of \'entilation and an apparent rise in the functional residual capacity. Beyond the third week there was little spontaneous mortality despite continued exposure and in animals sacrificed during this period, extensive areaS of edema were seldom seen..-\cute bronchiolitis and peribronchiolitis continued to be prominent (Fig. 4) and in some animals shortening and thickening of ah-eolar walls were obvious (Fig. 5). Later in this period, area,; of chronic bronchiolitis becanle more frequent and occlusion, partial or complete, by fibrous bands was eas\' to demonstrate (Figs. 6 and 7). Still other bronchioles appeared to be irreversihly scarred and obliterated so that their recognition as bronchioles was possible only due lo the persistence of small mucosal remnants. O\'erdistention of distal air spaces, including respiratory bronchioles, continued to be evident and areas suggesti\'e of breakdown of alveolar walls and coalescense of ah-eoli appeared for the first time. Such lesions were most frequently adjacent to tenninal bronchioles but, due to the lack of discrete secondary lobules in the dog, could not be called truly centrilobular. Focal area'i of atelectasis were noted in proximity to other occluded bronchioles, sometimes alternating with O\'erdistended spaces (Fig. i) . .-\t all stages, the bronchi and more proximal bronchioles were es.-;entially spared and extensi\'e damage was rarely seen proximal to the distal orders of ternlinal bronchioles. Two animals completed a 12 week exposure period and were then followed with weekly physiologic studies to detennine to what extent the physiologic changes were re\·ersible. In one dog, airway resistance had returned to nonnal by the eighth week, but in the other remained definiteh' elevated through the e1e\'Cnth week when he was

ROSSI:-I(; A:-ID CLAY

sacrificed. Nitrogen washout studie~ on both continued to show abnormal distribution of inspired air and increased functional residual capacity throughout the recovery period. This indicated that there remained regional disturbances in air conduction even in the animal wh"ose overall resistance to airflow was normal. Pathologic examination of the lungs of these two animals contirmed the presence of chronic obliterative bronchiolitis and an apparent reduction in the number of identifiable bronchioles. ~ticroscopic air space distortion was striking in some areas of these lun~ (Fig. 8) and for the first time a definite increase in the number and size of

Fm"RE 7 (upper): Two small bronchiol...s Colllplet...ly o<'C!ud...d by fibrous tissue with adjacent bands of partial atelectasis and. more ~ripheral\y. ar...as "C O\'er dist('nsion (X39). FIGI·Rf. 8 (lower I: Area of emphysema from do!( sacrifict'd t'ight wet'ks after last exposllfl' to phosgent' (X~3), Compare with fig. I, An increase in the nlllllbt'r and size of the larger air spaces is appar...nt. These appear to have arisen frum enlarg... ment and coa1(·s(·... nn· of alveolar ducts and distal respiratory bronchioles.

Diseas~s of

the Ch..t

ah'eolar pores could be seen (Fig. 10) as well as breakdown of alveolar walls. In summary, chronic exposure of dogs to phosgene regularly produced an acute bronchiolo-alveolitis which progressed to chronic occlusive and finally to obliterative changes in the bronchioles. :\ccompanying these changes there was alteration in pulmonar\' function which included three changes characteristic of emphysema: increased airway resistance. non-unifornl distribution of inspired gas and an increa<;e in the functional residual capacity. These functional changes were only partiallY re\'ersible up to eleven weeks after last exposure. Pathologically, the lungs of such animals showed microscopic changes quite compatible with earh' emphYsema, These included

FIGI'RE 9 (upper): Normal dog lung, air dri...d thick Sl'ction (X96) showing occasional alveolar purl'S in ah-eolar wall. seen en face, flGl'RE \0 I!owl'r): Air dried thick Sl'ction of the lung of a dog sacrificed thrl'e months after last l'xp<,sure to phosgene (X96). Note incfl'ase in size and nUJllber of alveolar pore.,

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rather severe distortion of the usual regular architecture of the lung, air space over distention and destruction and an increase in the number and size of interalveolar communications. DISCUSSION

We believe that the experimental disease here described resembles human emphysema cln~ely enough, physiologically and pathologically, to justify some tentative extrapolation~ from our observations to the human disease. Th~ experiments seem to support the concept that the basic lesion is. indeed, a bronchiolo-alveolitis. Durin~ the acute phase, ventilatory mechanics are markedly deranged, both by the exclusion from ventilation of large areas of lung by inflammatory edema and by the partial or complete obstruction of many bronchioles. Overdistention and hyperventilation of the remaining segments of lung may well result in stress on alveolar walls and connective tissue framework, but no evidence of tissue breakdown could be found at this time. The maintenance of aeration of alveoli whose supplying bronchioles appear occluded suggest that collateral ventilation through alveolar pores takes place, but not necessarily that it contributes to overdistention. After the subsidence of the edematous phase, evidences of chronic inflammation of the bronchiole and adjacent alveoli appear a.~ well a.~ acute lesions which continue to appear throughout the exposure period. The chronic bronchiolar changes include organization of the fibrinous exudate and the production of fibrous tissue bands which crisscross the lumen and partly occlude it. In some cases the occlusion appears complete whereas other bronchioles are completely obliterated. Evidence is thus seen for both partial and complete functional obstruction and aerated alveoli distally may presumably be ventilated either by inspiratory patency of bronchioles or by collateral routes. Other bronchioles are seen which are widely patent when fixed in the inspiratory position, but which appear to have lost external tractional sup-

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port and which may well collapse partIy or completely during expiration. Chronic changes are also seen in the alveolar walls which consist of stretching and thinning in some instances and shortening and thickening in others. The latter change may represent fibrous tissue proliferation within the alveolar wall or may be due to traction and retraction as discussed previously. It seems logical to expect that such altered septae might well be more prone to rupture under conditions of stres.~ due to uneven ventilation. Meanwhile increase in resistance and a significant disturbance in un if 0 rm it y of ventilation are found before evidence of alveolar breakdown is seen. This fact suggests that obstruction is due initially to direct inflammatory involvement of bronchioles rather than being due to loss of support. It does not, however, preclude a significant contribution by the latter mechanism later in the course of the disease. A definite increase in the number and size of alveolar pores was seen in the animals exposed for the longest period. Their late appearance indicates that they are not the primary lesion, but may rather be an intermediate lesion of importance in the breakdown of alveolar walls as described above. No special efforts were made to study either the vascular structure or the connective tissue elements so that our information to date sheds no light on the relative importance of these factors. As has been mentioned previously, the bronchi in these animals retained an essentially normal appearance. This is of interest especially in view of the frequent coexistence of chronic bronchitis and emphysema in the human. It would seem to indicate the importance of distinguishing between bronchitis and bronchiolitis. Chronic bronchitis has, until recently, been primarily a clinical term and defined in terms of a symptom complex. However, Reid l ' has recently proposed a pathologic basis for this diagnosis based on the ratio of the thickness of the bronchial glands to the thick-

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ness of the wall. This ratio was significantly increased in patients with clinical chronic bronchitis, but she describes a group of patients with emphysema without the clinical picture of chronic bronchitis in whom the ratio was normal. This corroborates the clinical impression that, despite their frequent coexistence, either emphysema or bronchitis may exist without the other. Because of the lack of a natural anatomic barrier between them it is to be expected that infections in the bronchi would frequently (but not invariably) also involve bronchioles and vice versa. If we regard bronchiolitis as the basic lesion of emphysema, we may reason that if inflammation remains localized to major bronchi. the clinical and pathologic picture of bronchitis may exist without emphysema. If, on the other hand, bronchiolitis exists without significant bronchitis such as has been artificially produced in the dog in these experiments, emphysema may develop in the absence of symptomatic bronchitis. The common association of the two conditions would be the result of infection or inflammation simultaneously involving both structures. Finally, some mention should be made of our choice of an experimental animal. McLaughlin. et aC··I. have studied the comparative anatomy of the lung in various mammalian species. They have developed a classification on the basis of the degree of lobulation, thickness of pleura, bronchovascular relationship, nature of the peripheral bronchioles and distribution of terminal vascular branches. In their classification, the horse is found to be most similar to the human and they suggest that the horse is the most suitable animal for experimental studies of emphysema. Aside from the ob,,;ous technical difficulty and expense involved in using the horse in a study such as ours, several other factors should be mentioned. Of the features utilized in their classification scheme, those most pertinent to this experiment seem to be lobulation and the nature of the peripheral bronchioles. Since no study was

made of the vascular structures, they will not be discussed. Well-defined secondarv lobules and interlobular septae, as the}: state, are absent in the dog lung and this prevents the categorization of the lesions seen in our animals with regard to location within the lobule. However, they found lobulation to be incomplete in the horse and the man and Anderson, et al.· confirm that the lobular organization is difficult to recognize especially in the central portions of the human lung. The incomplete nature of these septae in man also, as McLaughlin points out, permits collateral ventilation between lobules although possibly not as freely as in the dog. 'Vith regard to the nature of peripheral bronchioles, McLaughlin states that terminal bronchioles were absent in the dog and that the only form taken by the distal ailWays was that of highly alveolized respiratory bronchioles. Terminal bronchioles were present in the horse and man, but respiratory bronchioles were only poorly developed. In contrast to the latter finding, other investigators have described and demonstrated well developed respiratory bronchioles in man.·....1 In our material, these have been frequent in the dog, but we have also seen with regularity ailWay structures with no cartilage and no alveoli in their walls which we have called terminal bronchioles ( Fig. 1). Thus, it would seem that the peripheral bronchiolar distribution in men may be more similar to that in the dog than to that which McLaughlin, et ale have described in the horse, and that, for a studY of the effects of recurrent bronchiolitis th~ dog is quite a suitable animal. For a study of vascular pathology, of course this may not be the case. SUMMARY

Factors which have been suggested as being of importance in the development of emphysema are discussed and several schemes of pathogenesis composed of various combinations of these factors are reviewed. Recurrent exposure of dogs to sub-

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lethal concentration of phosgene gas produces a chronic bronchiolo-alveolitis. Physiologically, these animals show increased airway resistance, increased functional residual capacity and uneven distribution of inspired air, all of which are characteristic of emphysema. After several weeks of such exposure, they also show microscopic changes suggestive of emphysema. These experiments support the hypothesis that recurrent bronchiolo-alveolitis is the basic lesion in emphysema. They may also assist the further understanding of this disea~ by facilitating study of the correlation between changes in structure and in .function and by providing a model in which therapy may be evaluated. ZVS ..\M~fENF ..\ SSl· NG

Faktoren, die vermutlich fUr die Emphysementstehung von Bedeutung sind, werden diskutien und Moglichkeiten der Pathogenese, die sich aus verschiedenen Kombinationen dieser Faktoren ableiten, besproc hen. Wiederholte Einwirkungen subletaler Phosgenkonzentrate auf Hunde bewirkt eine c h ro n i s c h e Bronchiolo-Ah'eolit is. Physiologisch reagieren die Tiere mit einer Erhohung der Atemwegwiderstande, mit einer Erhohung des fllnktionellen Residllaivoillmens und mit einer ungleichmassigen Verteilung des Atemvolumens. All dies ist charakteristisch fiir ein Emphysem. Nach mehreren Wochen einer derartigen Exposition zeigen sie auch mikroskopische Veranderun gen im Sinne eine Emphysems. DieS(' Untersuchungen stiitzen die Hypothese. daP eine rezidi\'ierende Bronchiolo-Alveolitis die basale Schadigung fUr die Entwicklung des Emphysems darstellt. Sie mogen femer zu einem naheren Verstandnis dieser Erkrankung beitragen, indem sie das Studiums des Zusammenhangs zwischen strukturellen und fllnktionellen Veranderungen erleichtem und eine Modell fa II schaffen, indem der Therapeiffekt bestimmt .....erden kann. REFERENCES ROSSING, R. G.: "Pathogenesis of Emphysema," SAM Aeromedical Review, 5-64, USAF School of Aerospace Medicine, Brooks AFB, Texas. 1964. 2 SPAIN, D. M. AND KAUFMAN, G.: "The Basic Lesion in C h ro n ic Pulmonary Emphysema," Am. Ret'. Tuberc., 68: 24, 1953.

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3 McLEAN, K. H.: ''The Pathology of Emphy. serna," Am. Rev. Resp. Dis., 80(Supp) :59, 1959. 4 LIEBOW, A. A.: "Pulmonary Emphysema with Special Reference to Vascular Changes," Am. Rev. Resp. Dis., 80(Supp) :67, 1959. 5 ANDERSON, A. E., JR., Azcuy, A., BATCHELDER, T. AND FORAKER, A. G.: "Morphogenesis of Pulmonary Emphysema," Dis. Chest, 43: 350, 1963. 6 HEPPLESTON, A. G. AND LEOPOLD, J. G. "Chronic Pulmonary Emphysema-Anatomy and Pathogenesis," Am. ]. M.d., 31 :279, 1961. RICHARDS, D. W.: "Pulmonary Emphysema: Etiologic Factors and Clinical Forms," Ann. Int. Med., 53: 1105, 1960. 8 KRAHL, V. E.: "The Experimental Production of Pulmonary Emphysema," Am. Rev. Resp. Dis., 80(Supp): 158, 1959. 9 STRAWBRIDGE, H. T. G.: "Chronic Pulmonary Emphysema (An Experimental Study) I. Historical Review," Am. ]. Path., 37: 161, 1960. 10 STRAWBRIDGE, H. T. G.: "Chronic Pulmonary Emphysema (An Experimental Study) III. Experimental Pulmonary Emphysema," Am. ]. Path., 34: 391, 1960. II BoREN, H. G.: "Alveolar Fenestrae: Relationship to the Pathology and Pathogenesis of Pulmonary Emphysema," Am. Rev. Resp. Dis., 85: 328, 1962. 12 EBERT, R. V. AND PIERCE, J. A.: "Pathogenesis of Pulmonary Emphysema," Arch. Int. Med., III :80, 1963. 13 ROSSING, R. G.: "Experimental Production of Emphysema by Exposure to Irritant Gas," Transactions of the 21st Research Conference in Pulmonary Diseases, VA-Armed Forces, 251, 1962. 14 ROSSING, R. G.: "Physiologic Effects of Chronic Exposu re to Phosgene in Dogs," Am. ]. Physiol., 207: 265, 1964. 15 CLAY, J. R. AND ROSSING, R. G.: "Pathologic Findings in Experimental Exposure to Phosgene," Transactions of the 22nd Research Conference in Pulmonary Diseases, VA-Armed Forces, 146, 1963. 16 CLAY, j. R. AND ROSSING, R. G.: "Histopathology of Exposure to Phosgene," AMA Arch. Path., 78:544, 1964. 17 REID, L.: "Chronic Bronchitis and Hypersecretion of Mucous," Lectures on the Scientific Basu 0/ Medicine, 8:235, 1958-59. 18 McLAUGHLIN, R. F., TYLER, W. S. AND CANADA, R. 0.: "A Study of the Subgross Pulmonary Anatomy in Various Mammals," Am. ]. Anat., 108: 149, 1961. 19 McLAUGHLIN, R. F., TYLER, W. S. AND CANADA, R. 0.: "Subgross Pulmonary Anatomy in Various Mammals and Man," l.A.M.A., 175: 694, 1961. 20 McLEAN, K. H.: "Pathogenesis of Pulmonary Emphysema," Am. ]. Med., 25:62, 1958. 21 KRAHL. V. E.: "Microscopic Anatomy of the Lungs," Am. Rev. Resp. Dis., 80(Supp): 24, 1959.