anthracosis, now accepted as almost a physiological process

THE MIGRATION AND FATE OF THE MONONUCLEARPHAGOCYTE OF THE LUNG.*

H. H. PERMAR, PITTSBURGH, PA.

(From the Pathological Laboratories, University of Pittsburgh.)

Following in logical sequence to the study of endothelial re-actions in the lung, a detailed study of the function, migratoryactivities and fate of the pulmonary endothelial phagocyte isnecessary to gain a full appreciation of the life history of thiscell. In our previous studies (I920), which have been cor-roborated by the work of Foot (I920), certain principles re-garding the derivation of the endothelial phagocyte have beendetermined. It should be noted that all of this more recentwork on endothelial reactions in the lung only substantiates byexperimental method certain findings described by Haythornin I913.

In our previous work it was found that the large mononu-clear phagocyte of the lung is derived by proliferation fromthe vascular endothelium, and in large part that of the capil-lary network in the walls of the air sacs. This proliferativeactivity is accomplished by mitosis. The point of origin in thepulmonary capillaries is indifferent and determined only bythe proximity of an irritant in the lung tissue. The proliferat-ing cell is endowed with an ameboid motion, and once free,migrates directly to the site of the irritant, in the air sacs andbronchial tree. The point of entrance of the wandering cell intothe alveoli is equally indifferent, the cell passing directly be-tween the epithelial plaques to gain the free air space where itat once proceeds to collect within its cytoplasm the foreignsubstance which has called it forth. Ordinary pulmonaryanthracosis, now accepted as almost a physiological process,illustrates how slight an irritant may give rise to a proliferativeendothelial reaction.

* Received for publication December 30, I920.

It is the object of this paper to describe the phagocytic andmigratory activities of the endothelial phagocytes in the lungchiefly from the standpoint of their reaction to inert particu-late matter. Here we have to deal with phases of endothelialactivity which are in no way related to blood vessels or theblood stream.

The experimental work insofar as this phase of the study isconcerned was extremely simple, consisting merely in intra-tracheal injections under ether anaesthesia of one to two cubiccentimeters of a suspension of powdered carmine in salinesolution, allowing the animal to live for varying periods oftime up to six days following the injection. The plan of com-bininig with this the intravenous injection of a benzidine dyeor a comparable suspension of finely particulate matter withthe aim of marking wandering or proliferated endothelial cellsfor identification is as old as is the experimental study of themononuclear cells of the lung, having been employed bySlavjansky (I869), and with some modification, by Tchis-tovitch (I889). This was the method employed in our previ-ous studies for the identification of the endothelial phagocyteand in the study of its origin. The reader is referred to theprevious papers for the details of this work. Other materialswere also tried. A few animals received intratracheal injec-tions of 0.5 per cent solutions of isamine blue, others of lithiumcarmine while in some of the earlier experiments suspensionsof ferric oxide, cinnabar, and vermilion water color pigmentwere employed. The whole series included twenty-threeanimals. All showed the same result as far as phagocyteactivity is concerned; that is, the phagocytosis of the injectedpigment began almost at once, being first taken up by the dustcells (endothelial phagocytes) present in the alveoli at the timeof the injection. After one hour the phagocytic cells hadslightly increased in number, and more pigment had been en-gulfed. This was illustrated in three animals. This processprogressed until in two animals killed at the expiration oftwenty-four hours, practically all the pigment was intracellular,even where the pigment was present in large quantities. In

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reviewing the literature, one encounters reports of the useof all the above substances, as well as other inert materialssuch as indigo, ultramarine blue, and carbon in a varietyof suspensions. Likewise many types of bacteria, and evensuch materials as the washed red blood cells of the sameor unrelated species of animals have been employed, thenucleated red blood cells of birds, selected because they maybe readily identified in section, being used by several. Withall of these widely diverse materials the endothellal phagocytewas the cell found most active, as can also be deduced fromthe descriptions of the various previous investigators. Theconclusions offered in these earlier studies and even some offairly recent date, were quite diverse. Some earlier workersthought of a connective tissue origin, or confused these cellswith the mononuclear group of the circulating blood. Therewere also those who believed that the epithelial lining of theair sacs, either by desquamation or proliferation produced themononuclear phagocytes of the alveoli and this view, basedentirely on a superficial morphologic similarity, has againrecently been advocated (Sewell, I919). The discussion ofthis phase of the problem need not be repeated here.The phagocytic activity of the endothelial phagocytes as

demonstrated in these experiments was never sufficiently greatto ingest all the free pigment in the alveoli within five hours;but as indicated, the close of a twenty-four hour period (asillustrated in two animals), found all the foreign particlesintracellular. These cells take on the most extraordinarilyheavy loads of pigment, even when the particles are relativelycoarse. As a result, they increase enormously in size and thenucleus becomes completely masked by the quantities ofgranules with which the cytoplasm is packed.We have thus shown the site of origin of the dust phagocyte,

its mode of origin, its manner and place of entrance into the airsacs, as well as its activities under certain conditions as a freephagocyte. Remaining to be considered are the point of exit,subsequent migratory activities and eventual disposition ofthese cells; and as these studies cover only the early period ofthe reaction (from one hour to six days), the propprtion of

21II

mononuclear phagocytes leaving the alveoli during this periodis also of interest.Though the foreign pigment is entirely intracellular at the

end of a twenty-four period, the endothelial phagocytes do notleave the alveolus at a rapid rate. On the contrary, there isoften very little difference in the picture even at the end1 offive or six days. In four animals killed after this interval, thealveoli still seem equally crowded by the same groups of largeheavily loaded cells. This is borne out by the relatively slightchange in the number of cells found migrating along thelymphatics after six days as compared with that found aftertwenty-four hours. In fact, in some animals there seems to bea slowing down after the first acute reaction, and the migrat-ing cells are even fewer in three to five days than after twenty-four hours, indicating a lessened activity after the acutenessof reaction is gone. The actual time period required to effectcomplete clearing of the alveoli could only be estimated byexperiments covering long periods of time, possibly even run-ning into months.

Quantitatively there is no comparison between the anthra-cotic process and this type of experimental procedure. It isa well known fact that the former develops extremely slowly,the phagocytes apparently only leaving the alveoli after theyhave taken on a considerable amount of pigment; at least,they invariably show fair amounts of it when found ininterstitial positions, in lymphatics, lymphoid collections andnodes.

It is possible that by the intense overloading following theexperimental injection of particulate matter the cell is renderedincapable of ameboid; movement to the normal degree, or itmay be that there are changes brought about in the alveolarepithelium during the early period of the reaction which makeit more difficult for the wandering cell to penetrate this layerin great numbers.The smaller bronchioles, which in the early hours and up to

the end of a one day period contain quantities of carmine pig-ment, are much more readily cleared. This in part is accom-plished by the action of the ciliated epithelium, which sweeps

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both free and phagocyted pigment upward to be expelled inthe sputum. It must be noted that in these fine air passages,the endothelial phagocytes are definitely active. Further, asMiller has shown, numerous isolated air sacs are distributedin bud-like fashion along the terminal bronchioles (bronchiolirespiratorii). These doubtless produce from their vascularendothelium the phagocytes that perform this function. Manyof these wander to the adjoining proximal bronchioles havingciliated epithelial lining, whence they are carried outwardthrough the main air passages. And further, the ready accessto the peribronchiolar lymphatics which is afforded to phago-cytes active in this region accounts for the readiness withwhich the finer air passages are cleared.The path of exit from the alveoli is by no means as indiffer-

ent as the point of entrance. One rarely finds carmine bearingphagocytes reentering the thin walls of the sacculi or thealveoli pulmonis. Instead, they almost uniformly seek thesomewhat heavier walls of the atria, as though aiming to reachthe terminal lymphatics originating about the ductuli alveo-laris. Moreover, in those instances where the walls of thealveoli are found invaded by the pigment bearing phagocyte,it is usually possible to suggest that this alveolar structure isone of those arising directly along the course of the terminalbronchioles. With a little consideration of the structure ofthe pulmonary saccules, it is seen that while proliferatingendothelial cells may readily extrude themselves from withina thin membrane or septum of this sort it offers them littleopportunity to migrate along the interstitial planes. On thecontrary they may with ease progress along the surfaces ofalveoli and sacculi, reaching the atria and even the alveolarductules before taking up interstitial migration.

It must be admitted that in the present experimental methodthe injected particulate substance is more largely deposited inthe atria than elsewhere, though a good distribution through-out the air spaces of the anatomical unit of the lung wasusually attained. Anthracosis, however, presents the samefeatures as regards the point at which the dust cells enter theinterstitial tissues, and the suggestion of a greater tendency

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PERMAR

to migrate into the atrial walls depending on the experimentalprocedure can be definitely ruled out.Another more simple point of exit from the air spaces is by

direct migration along the ductulus alveolaris and the contigu-ous respiratory bronchiole to reach the fine bronchioles linedby ciliated epithelium, whence the cell is fairly rapidly movedto the bronchi and trachea and finally expelled in the sputum.Such cells, well loaded with carmine granules, may be foundin the bronchi and trachea of these animals five and six daysafter intratracheal carmine injections. It has been shown thatafter a single injection given in the manner described, the airpassages are cleared of free pigment granules within twenty-four hours. Hence it appears that certain of the alveolarphagocytes are constantly leaving the body in this way. Astriking demonstration of this fact may be made by anyoneliving in the smoky atmosphere of our large cities by simplypreparing a film under a coverglass from the small blackishnodules in the sputum, in which may be found numerous roundendothelial phagocytes so finely stippled with granules ofcarbon as to require high power examination to identify theindividual particles. Without question these cells have comein large part from the air spaces, because of the fineness of theparticulate substances they contain. Also, it has been shownexperimentally and by study of anthracotic lungs that only aminimum of phagocytic activity goes on in the upper passages(Haythorn).A third route of exit may be mentioned if for no other reason

than to point out that it does not occur, so far as the study ofexperimental or human tissues is concerned. This is by re-migration into the capillaries and finer vascular channels ofthe lung. There is as yet no evidence that such an event evertakes place. Entrance into the systemic circulation, however,is a possibility which will be discussed further.

It is worth while to emphasize here the fact that free pigmentdoes not gain entrance to the lymphatics. It is always in-tracellular when it enters the interstitial tissues. This doesnot mean however that free pigment may not be found inthese situations temporarily since of course the wandering

2I4


phagocytes, while evidently long lived, may undergo death anddisintegration at any time in their career, thus liberating thepigment they carry. Such pigment must remain free only fora short period, until taken up by other nearby phagocytes.In the experimental work on the lung, pigment was not foundfree in interstitial tissues or lymphatics in any instance. Andin anthracotic lungs the same is broadly true though here wehave to do with a slow and long continued process in whichwandering phagocytes of all degrees of senility are concerned,and one may occasionally find them undergoing disintegration.This occurs most frequently in the anthracotic nodules char-acteristic of the advanced stages of the condition, in whichrepeated blockage of lymphatics by large numbers of dust cellsis accompanied by a slowly developing irritation fibrosis.Eventually there is formed a definite, palpable nodule of densehyaline connective tissue having a concentric arrangement,with cleft-like spaces containing many compressed phagocytes.These gradually degenerate in their isolated situation andothers are unable to reach the pigment so liberated. Hence,as Osler (I876) indicated in a masterly exposition of the prin-ciples involved in pulmonary anthracosis, the fluid expressedfrom such a nodule shows many "ameboid corpuscles" filledwith black granules and it is mainly on these that the darkcolor of the nodule depends, but also there are found in thisfluid quantities of free black granules. This, then, is the onlyinstance of foreign particulate material long remaining free inthe lung tissue. Naturally, in progressive destructive lesionsof both acute and chronic types the intracellular pigmentlodged in the stroma may be liberated. But this is outside theprovince of our present theme, which is solely to establish theimportance of the endothelial phagocyte as the agent dealingwith inert particulate substances in the lung.Once having gained the lymphatics the ameboid activity of

the endothelial phagocyte is further called into play as a meansof progress until the very wide channels are reached, where itis possible that a degree of onward movement is brought aboutby the flow of lymph. This factor is apparently slight even inthe largest lymphatic channels in the absence of pathological

2I5

states, since in experiments on the tracheal lymphatics madeby injecting a suspension of carmine into the vicinity of boththe deep and superficial plexuses it was found that even aftersix days there were no carmine bearing phagocytes in theperibronchial lymph nodes, and only a few had migrated alonglymphatics to a distance of a few millimeters toward the lowerend of the trachea.

Experimental study of the carmine injected lungs revealstwo important facts in regard to the rate of progress of whichthe endothelial phagocytes are capable in lymphatics, (i) theyreach the sinuses in the cortex of the peribronchial lymphnodes within twenty-four hours, though only in small num-bers, and (2) the great majority of loaded phagocytes have noteven left the air spaces after a period of six days. Some fewphagocytes may be seen to have taken up interstitial positionseven after two to three hours (in three animals), and they aremore numerous after six hours (one animal), at which timethey may also be found in lymphatics and the small lymphoidcollections of the finer stroma. After twenty-four hours (twoanimals), they have traversed the whole lung, and occur inthe lymph nodes at the hilus. At this period they may befound, in scant numbers in the lymphatic channels at all pointsleading to the hilus. From this stage there is but little changein the distribution and abundance of loaded cells wandering inlymphatics up to the five day period (three animals), afterwhich there seems to be a decreased activity of migration fromthe alveoli, as the lymphatics of the stroma show fewer cellsalong their course after five and six day intervals (in oneanimal), following intratracheal injection. In the naturalanthracosis of animals as well as of the human we have, how-ever, definite proof that the phagocytosis of inert materials inthe lung and the transportation of these within the cytoplasmof the endothelial phagocytes to their final depot in peri-bronchial lymph nodes is constantly though slowly going on.This is best illustrated in early anthracosis as found in youngindividuals and in experimental animals, where one may seeaccumulated carbon bearing phagocytes in the peribronchiallymph nodes in sufficient numbers to produce a gross grey

2I6 PERMtAR


color while the lungs, though showing a mild anthracosismicroscopically, present no gross evidence of it.During their migration along lymphatics, the endothelial

phagocytes encounter the numerous small lymphoid collec-tions of the stroma which lie at the points of branching of theair passages and of the pulmonary artery. They wander intovery fine channels in these nodes where they may constantlybe found in small numbers though there is no tendency forthem to accumulate in these regions. The same is true inanthracosis; they are constantly present and appear to aggre-gate here, though the heaviest accumulations and the forma-tion of anthracotic nodules within the lung occur in the lym-phatic channels and at the small dilatations occurring at theirpoints of junction. This is especially well demonstrated in thepleura of anthracotic lungs, as has been pointed out by Klotz(I914).The final depot for pigment and dust bearing phagocytes is

the lymph nodes at the hilus of the lung. Here they enter firstthe marginal sinus, then the fine sinuses ramifying through thecortex of the node, appearing largely in the pulp and to a lesserextent in the follicles, and finally they also come to lie in thesinuses of the medulla. In extreme anthracosis of these lymphnodes the phagocytes appear to have invaded the entirestructure, lying within pulp as well as in sinuses. Those occur-ring with carmine particles in the peribronchial lymph nodesof the experimental animals lay in fine sinuses and sometimesapparently in the pulp of the cortical zone. In the earlyanthracosis seen in experimental animals the inner zone of thecortex shows the bulk of the pigment bearing cells with manyalso in the sinuses of the medulla. In the human, one ordi-narily sees a well diffused distribution of phagocytes through-out the node.

The fate of the mononuclear phagocytes once they havereached the lymph nodes at the hilus is practically limited totwo or three events. But before discussing these it might bewell in considering the fate of these cells to refer again to theirdirect final disposition by migration from the air sacs and

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PERMAR

terminal bronchioles into the ciliated air passages and theirsubsequent expulsion in the sputum. Those, however, whichmigrate through the lymphatics finally to reach the lymphnodes at the hilus have by that means achieved the end of theirwanderings. Here they ordinarily remain quiescent for longperiods. In anthracotic lungs, too, many migrating cells be-come blocked in narrowed and obstructed lymph channels andremain incarcerated indefinitely in these situations. The pig-ment bearing cells in this stage assume a flattened, fusiformshape and bear a decided resemblance to fibroblasts.When, however, an acute inflammatory reaction with

oedema supervenes or, in animals, when oedema of tissues isinduced experimentally, as has been shown by Haythorn, thevery flattened cells rapidly become rounded in outline andagain show evidence of phagocytic activity and ameboidmovement. This is often beautifully seen in the type of acuteperibronchial lymphadenitis accompanying lobar pneumonia,and especially in that seen with the influenza pneumonias.The striking feature in these lymph nodes is the presence in thewidened sinuses of numerous heavily loaded mononuclearphagocytes. They are largely the result of remigration of thephagocytes of the lymph node, reactivated from their dormantstate. Some, however, may have recently arrived from thelung since the dormant dust cells of the pulmonary stroma arereactivated in the same way. This brings up further possi-bilities in the fate of the endothelial phagocytes. The fore-going would indicate reactivation and remigration to a siteof injury where possibly many perish while others again withthe subsidence of the inflammation may return to a quiescentexistence in lymphatics or lymph nodes. An additional possi-bility and one for which experimental evidence is wanting,though there are some very suggestive data available from thestudy of human tissues, is that of the sweeping of phagocytesfrom the sinuses of the lymph nodes into the thoracic duct andthence to the systemic circulation. This would seem to beparticularly likely under conditions of intense oedema withmany phagocytes free in the widened sinuses of the lymphnode.

2I8


Either of these events would tend to clear the lymph nodesof the accumulation of years. In the lung much the sameprocess takes place and large quantities of phagocytes thathave been able, following reactivation, to reenter the alveoli,unquestionably are destroyed and excreted in the profusesputum of acute pulmonary inflammation. Such others as areable to enter again the lymphatics may subsequently gain thelymph nodes following the inflammatory clearing of blockedlymphatics, provided fibrosis has not occurred, or they maymerely contribute to the quota normally lodged in the lungstroma.

The foregoing report, based on an experimental study fromthe aspect of their reactions to inert particulate substances ofthe mononuclear (endothelial) phagocytes in the lungs oftwenty-three animals indicates that such substances, whenthey gain entrance to the alveoli, attract the mononuclearphagocytes and even induce their proliferation from the endo-thelium of the capillaries in the alveolar walls. Though it hasbeen shown that certain of the phagocytes may wander out-ward along the air passages to be expelled in the sputum, themore important mode of disposal of intra-alveolar foreignparticulate material in lungsfree of inflammation and oedema isthrough the invasion of the pulmonary tissues by the mononu-clear pigment bearing phagocytes. This occurs mainly throughthe atrial wall, as the terminal lymphatics are readily acces-sible from this point. The mononuclear phagocytes pursue aslow, uncertain course along the lymphatic channels andnumbers of them eventually reach and become stationary inthe lymph nodes at the hilus. These findings are directlycomparable to those described in the studies on anthracosisbrought out by Haythorn and Klotz a few years ago (19I3-1914), and are supported by them. It is interesting to observethat a sudden flooding of the air sacs with particulate matter,as was done in our work, is dealt with in exactly the same wayas is the constant slight influx of a few fine carbon and dustparticles. This is as far as the resemblance of this experi-mental work to true anthracosis can be carried. The various

2I9

end results of long continued dealing with inhaled particulatematter, and the bearing that these end results have on thestate of health of the normal individual and on the lung changesduring superimposed disease processes, have been discussedby Klotz. These chronic reactions to particulate material inthe lung do not lend themselves to experimental reproduction,and in their advanced grades must be studied in human tissues.

Experimental injection of carmine suspension into the re-gions of the deep and superficial lymphatics of the tracheawithout allowing the material to enter the air passage hasalready been mentioned. This was undertaken primarily todetermine to what degree carmine that might be phagocytedby wandering mononuclears in the trachea and large bronchiwould contribute to the presence of carmine bearing cells inthe lymph nodes at the hilus, and whether this would accountfor the presence of these cells in the peribronchial lymph nodesat the early interval of twenty-four hours after intratrachealinjection of carmine. Three rabbits were used in the workand intervals of four to five days were allowed to elapsebefore killing the anIimals in which such injections had beenmade. The gross examination of the trachea from thelarynx to well past the bifurcation and including the lymphnodes of the hilus showed no evidence of diffusion of car-mine upward and downward; it could be detected only adistance of a few millimeters even when the serial crosssections were studied with a hand lens. No evidence ofred color appeared in the lymph nodes of the thorax. Sec-tions were made from selected blocks, one taken near thelower end of the larynx, one through the area of carmine in-jection, one or two at points between the injected area and thebifurcation and one at the bifurcation of the trachea includingseveral of the peribronchial lymph nodes. The microscopeconfirmed the gross findings. The local site of carmine depositshowed the pigment granules all located within endothelialcells. Some few of these had entered the lymphatics, chieflythose of the deep set, mainly because these were closer to themass of injected granules. But none of these had advanced

220 PERMKAR


down to the level of the first section below 'the site of the in-jected pigment, that is, between i.o and I.5 cm. from the pointof injection. There was no microscopic evidence of either freeor phagocyted carmine in the lymphatics of the trachea at itstermination nor in those of the bronchi just beyond the bifur-cation. And the lymph nodes were likewise negative both forfree and intra-cellular pigment. The carmine was certainlymade available for phagocytosis close to the large lymphatics,some no doubt even being placed directly into these channelsat the time of inje'ction. That the pigment is taken up byendothelial phagocytes, and that they enter the tracheallymphatics has been cle'arly shown. But it is also clear thatin the absence of active inflammation, such as may be inducedby pathogenic bacteria, there is a very slow passage of endo-thelial phagocytes along these channels toward the hilus, andfurther it appeared that the wash of the stream must be ex-tremely slight, indicating that ameboid movement is largelyresponsible for the progress of the endothelial phagocytes evenin the largest lymphatics.A similar study of the trachea of six animals receiving simple

intratracheal injections of carmine suspension and killed at in-tervals of three hours, six hours, twenty-four hours, and three,five and six days following the injection, revealed active phag-ocytosis by endothelial mononuclears beginnlng after sixhours on the mucosal surface of the trachea and large bronchi.Within this time none of the carmine bearing cells had reachedthe tracheal lymphatics, however. None were found in lym-phatics after twenty-four hours. After three days some oc-curred, though few, and'these may have come from the slightinterstitial deposit of carmine consequent upon the passageof the needle through the tracheal wall. There was no evidenceof migration through the tracheal wall. The trachea at thistime contained small clumps of carmine loaded phagocytesenmeshed in a thin mucoid material. These may have comeupward from the finer structures of lung. There was no freecarmine at this time. After the lapse of five days, the tracheallumen showed no carmine, either free or intracellular, andagain no phagocytes were seen migrating through the tracheal

221

wall. The granules deposited in the tissues of the trachea bythe passage of the needle were all intracellular and some of thephagocytes had reached lymphatics, but had only migratedfor a distance of a few millimeters. The same findings occurredafter six days.

It would seem to be clear, then, that while particulate ma-terial may be phagocyted to a degree in the lumen of thetrachea or large bronchi, very little if any direct inward mi-gration through the walls of these structures takes place. In-stead, the phagocytes appearing here are lost to the bodythrough the sputum. Further, that phagocytic cells are notrapidly carried to the pulmonary hilus in the large tracheallymphatics in the absence of an active inflammatory reactionin the tissues of the trachea is also evident. Their move-ment in this direction has been shown to occur, but veryslowly.The pigment reaching the air sacs at the time of the injection

is sufficiently irritating to induce an active proliferation ofendothelial phagocytes, which within twenty-four hours haverendered practically all of it intracellular and presumablyharmless. That a moderate degree of acute inflammatory re-action is at first induced, with some dilatation of lymphaticsand possibly some increase in rate of lymph flow, would appearto be indicated. Or it may be that the ameboid movement ismore rapid in certain of those cells which in the air sacs arecalled forth more rapidly than they are in the trachea. Atany rate, it is clear that the few carmine bearing phagocytesappearing in the peribronchial lymph nodes within twenty-four hours after the carmine granules had been deposited inthe lung do come from the air sacs along the lymphatics of thelung stroma, and not directly through the tracheal lymphchannels either as a result of having been deposited intersti-tially by the needle or by migration from the tracheal lumen tothe lymphatics. Thus Haythorn's contention that the activityof the endothelial phagocytes against particulate matter in thelarge air passages is slight is again borne out by experimental

222 PERMKAR


evidence. That these channels are at a disadvantage inthis regard as compared with the air sacs with their numeroussuperficially located capillaries is worthy of note, though thislack is largely compensated by the function of their ciliatedepithelial lining.

It would seem that this method of study of the endothelialphagocytes cannot always be interpreted in terms of directcomparison with the reaction of these cells to bacteria. How-ever, the activities of the endothelial phagocytes in the tracheaand bronchi have been shown, and their tendency to followlymphatics to the hilus has also been demonstrated. Thechief point lacking to make comparison complete is the rateof the reaction. In acute inflammatory reactions of the lung,recently shown by Blake and Cecil (I920), and Winternitz(I920), to originate in the trachea and main bronchi and in-vade lung parenchyma primarily by lymphatics, there mustexist, as suggested above, other important factors making therapid diffusion possible. Of course, the r6le of the polymor-phonuclear leucocytes has not even been considered in con-nection with our own work, since they are virtually inert tomaterials such as carmine. These cells are those most activelyconcerned with the phagocytosis of the large group of pyo-genic bacteria. They, however, are in turn taken up by theendothelial phagocytes, especially when moribund or degene-rating as after engulfing virulent organisms. The possibilitythat infection may reach the tracheal lymphatics in this way,even in the absence of a true ulcerative lesion of the trachealmucosa, still remains. That with given changes in the lym-phatic channels and lymph flow this infection could be diffusedto the hilus and also throughout the stroma of the lung mustbe admitted. The possibility of a few tubercle bacilli gainingentrance directly to the peribronchial lymph nodes by phag-ocytosis from the tracheal lumen must stand, as nothing inthe experimental evidence controverts it. But it would seemfrom this work that the greater likelihobd is that the tuberclebacilli giving rise to isolated foci in the peribronchial lymph

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nodes are carried there by endothelial phagocytes from air sacsor terminal bronchioles.

Aside from the interest we may have in anthracosis and inexperiments more or less simulating this condition from thestandpoint of a cytological study or of one having a bearing onthe broad problems of the development of inflammation in thelungs, we may, in closing, sum up the case for anthracosis as adefense mechanism in the words of Osler, who in I876 wrotethat in the event of dust getting into the terminal bronchiolesand air sacs, where the ordinary defenses are wanting, "natureprovides that they shall, at any rate, be placed in less injuriouslocalities." Osler did not know how to classify the "ameboidcorpuscles" he saw and described, but leaned to a connectivetissue origin, thereby approaching the present conception inso far that he placed them as originating locally from the fixedtissues. He commented with evident interest on the size andnumber of these cells, and noted characteristically that "atleast the supply was equal to the demand." Further, and hisfindings were remarkably substantiated in the lungs of theserous influenza pneumonias, he noted that "even excessiveloading of the cell by carbon had no apparent ill effect on itsbiological activities." This was remarkably well shown in thematerials cited, in which the stroma not uncommonly wasalmost cleared of phagocytes, which had abandoned theirspindle shape and secluded locations in the finer lymphatics ofthe stroma to appear, though heavily loaded, as active phag-ocytes in the air sacs. In the clearer knowledge of our dayconcerning endothelial reactions, Osler's little known articleof I876 is extremely interesting, and further, has a most re-markable wealth of correct observation and almost intuitivededuction compressed into the few pages he gives to the prob-lem of pulmonary anthracosis.The writer's thanks are due Professor Oskar Klotz for his

interest in this work during its progress, and his critical sug-gestions during the preparation of the report.

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MONONUCLEAR PHAGOCYTE OF THE LUNG 225

BIBLIOGRAPHY.

Blake and Cecil. Journ. of Exper. Med., I920, xxxi, 445.Foot. Journ. of Exper. Med., I920, XXXii, 533.Haythorn. Journ. of Med. Res., 19I3, XXiX, 259.Klotz. Amer. Journ. Public Health, I914, iV, 887.Osler. Canada Med. and Surg. Journ., I876, iV, I44.Permar. Journ. Med. Res., I920, Xlii, 9.Permar. Journ. Med. Res., I920, Xlii, 147.Sewell. Journ. of Path. and Bact., I9I8, Xxii, 40.Slavjansky. Virchow's Archiv., I869, xlviii, 326.Tchistovitch. Annales de l'Inst. Pasteur., I889, lm, 337.Winternitz, Smith and Robinson. Bull. Johns Hopkins Hospital, I920,

xxi, 63.

anthracosis, now accepted as almost a physiological process

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