S14 Thorax 1994;49 Supplement:S14-S18

Carotid bodies in animal models of human Thorax: first published as 10.1136/thx.49.Suppl.S14 on 1 September 1994. Downloaded from disease: what do they teach us?

Gwenda Barer

Animals suffer their own diseases and rarely Hypoxic carotid body in man and animal afford us accurate pictures ofhuman afflictions. "models": morphology and physiology The argument is cogent that we can only learn In 1970 Heath and colleagues published a about human problems through the study of paper describing the carotid bodies in 40 con- humans. However, had we never investigated secutive necropsies. The weight of the carotid animals there are things we certainly would body was high in patients with emphysema, never have known. I contend that we would Pickwickian syndrome, and cor pulmonale, and not have discovered the respiratory function of a significant correlation was observed between the carotid body. In anaesthetised animals we the combined weights ofthe carotid bodies and can humanely cut and record from nerves, the weight of both the right and, unexpectedly, change gas tensions, give drugs and poisons. the left ventricle.3 In 1971 a further paper Animals can be exposed to environments which confirmed these findings.4 affect humans under controlled conditions, and In the following years the Liverpool group then compared with normal animals of similar produced a series of fascinating papers on rats age, sex, and life experience. Then there is the exposed chronically to hypoxia in a hypobaric morphological problem. Animal tissues can be chamber. They showed that the carotid body taken at the moment of death or before, so that enlarged rapidly, developed vascular en- the autolytic problems which beset pathologists gorgement and cellular changes at both the do not hold. All these points apply to research light and electron microscopic levels, and re- on the carotid body, to the interaction between turned to normal rapidly in air.5 Others con- physiologists and pathologists, and the argu- firmed these findings. In collaboration with ments between them. Much has been learnt Dr Edwards from the Liverpool group our from the efforts of these two groups but few Sheffield team showed similar morphological problems are wholly settled; the disputes be- changes in rats kept in both hypobaric and tween different disciplines often point the way normobaric hypoxic chambers.6 In Prague

forward to further research. In talking about Herget, in collaboration with us, found http://thorax.bmj.com/ "models" we should consider how far they enlargement of the carotid body in rats with reproduce both morphological and functional experimental silicosis and emphysema, the size features of human conditions. being proportional to the degree of hypoxia in life.7 In Sheffield we found functional changes attributable to the carotid body in our chron- ically hypoxic rats.' When removed from the chamber and given low oxygen mixtures to Historical breathe they increased their ventilation to a Study of the human carotid body gathered lesser degree than normal rats (figure). This on September 27, 2021 by guest. Protected copyright. impetus when Arias-Stella found that it was excited us because high altitude dwellers in unusually large in people in the high Andes both the Andes and the Himalayas have a who had lived all their lives in an hypoxic en- "blunted" ventilatory response to hypoxia, as vironment.' At this time Professor Heath was do children hypoxic from congenital heart dis- studying patients with chronic bronchitis and ease. The "blunting" in rats lasted only a few emphysema who were hypoxic because they days into recovery in air, but the finding has could not take in sufficient air. He found been repeated many times. About this time it changes in their pulmonary vessels similar to was shown by the group in Denver, Colorado those found in high altitude dwellers. He began that non-native residents at high altitude de- to look at their carotid bodies and found them velop "blunting" after about 12 years' res- also to be abnormally large. In Sheffield we idence.8 More recently the Denver group have were studying rats and mice made hypoxic in shown that "blunting" in women living at high a hypobaric chamber and had sent Professor altitudes in Peru is "reversible" in that a brisk Heath some slides of their lungs. He replied ventilatory response to hypoxia returns to with enthusiasm that their small lung vessels these normally blunted individuals during resembled those of his bronchitic patients. At pregnancy.9 Thus blunting may be switched on a meeting of the Pathological Society in and off. Flenley and colleagues showed that a Sheffield in 1970 he gave a paper on human proportion of patients with chronic hypoxic carotid bodies and we gave one on pulmonary lung disease have a poor ventilatory response vessels in our hypoxic mice.2 We met and both to hypoxia.'0 To this point human and animal Department of decided to look at carotid bodies in animals studies concurred, but more detailed mor- Medicine, Royal in a low oxygen environment - in "animal phological investigations led to a divergence. Hallamshire Hospital, kept Sheffield S10 2JF, UK models of hypoxic lung disease". Thus began In rats chronically exposed to hypoxia with G Barer a long friendship and collaboration. or without hypercapnia morphometric analysis Carotid bodies in animal models of human disease: what do they teach us? S15

175- A - Normoxic appearance was found by Habeck in some of + zC} Chronically hypoxic his hypoxic patients.15 The question was raised Thorax: first published as 10.1136/thx.49.Suppl.S14 on 1 September 1994. Downloaded from E 150 as to whether this appearance was related to the advanced age ofmany ofthe patients compared E 125 with the youth of the rats. A study of changes + + in the human carotid body with age showed 0o 100 _ + that this was not so, although sustentacular r- > became more common as life ad- w <+ proliferation 75 + + vanced.'6 Nonetheless one cannot compare the + carotid body of a human coming to necropsy 50 after a lifetime of repeated illnesses and 2 5 5 0 7 5 10 0 12 5 15.0 17 5 20 0 experiences with that of a rat dying after Pao2 (kPa) a sheltered healthy life and brief hypoxic This is unresolved. 125 B 4111~- Normotensive exposure. problem 12-+ Hypertensive Do chronically hypoxic rats, therefore, more 100 O closely resemble high altitude dwellers than .E ++ hypoxic patients? This may be so. Arias-Stella + + and found that the carotid body of 757 Valcarcel'7 0 + Quechua Indians contained larger and more C,) 50 e i numerous lobules than that of plain dwellers, 0 i0 due to proliferation of "chief cells" with thin uw 25 intervening fibrous tissue. Recently Professor Heath's group have looked at carotid bodies of 0 four high altitude dwellers from Ladhak in the 2 5 5 0 7 5 10 0 12 5 15-0 17 5 20.0 Karacorams.'8 The carotid body was ab- Pao2 (kPa) normally heavy in the two oldest subjects. In Re lation between ventilationIlOOg body weight and three cases there were numerous clusters of arterial Po2. Values are means (SE.) (A) Chronically chief cells with many of the "dark" variety, hylpoxic rats increase ventilation less than control rats with which have been found both in young and old increasing hypoxia. (B) Hypertensive rats ventilate more thcin normotensive rats over a wide range of Po2 but the cases of hypoxaemia. Only a 52 year old man increase in ventilation with increasing hypoxia is similar. had sustentacular cell proliferation. We must Dcita derived from refs 21 and 29. look at rats after repeated or very long hypoxic exposures to see if they develop sustentacular hyperplasia. It may eventually be proved, how- showed that the enlargement of the carotid ever, that rats and humans are fundamentally bc,dy was partly due to vascular engorgement different.

but also to proliferation of type 1 (often called http://thorax.bmj.com/ chief) cells and connective tissue cells; there was also angiogenesis." The dense-cored ves- Biochemical changes in the hypoxic icles in type 1 cells, which contain dopamine, carotid body: functional consequences were changed morphologically and the number In the 1970s and 1980s electrochemical ana- per carotid body was greatly increased. The lyses showed that the catecholamine content of proliferation of type 1 cells was at first disputed the carotid body in rats altered during hypoxia. since they were thought to be neural in origin; During chronic hypoxia the noradrenaline and hyperplasia was proved conclusively when mi- dopamine contents increased dramatically, on September 27, 2021 by guest. Protected copyright. toses were found after arrest of cell division and returned slowly to normal during recov- with vincristine.'2 Autoradiographs taken after ery in air.'9 The turnover of dopamine also administration of tritiated thymidine showed increased.20 Dopamine inhibits the response of numerous cell divisions 1-4 days into hypoxic the carotid body to hypoxia; it diminishes both exposure.13 No change was detected in the type the frequency of impulses travelling up the 2 cells which normally envelop the nests of type carotid nerve and the subsequent increase in 1 cells. The carotid body therefore appeared to ventilation. We wondered ifthe "blunting" seen be hyperplastic and active as one might expect in our rats could be due to the high content of under chronic stimulation. dopamine in their carotid bodies. We found, By contrast, in the enlarged carotid body indeed, that a dopamine inhibitor, dom- of patients dying from hypoxic lung disease peridone, increased ventilation during hypoxia Professor Heath's group found a hyperplasia in both normal and chronically hypoxic rats which consisted of concentric whorls of but more so in the latter, so that their ventilation "sustentacular" cells (resembling type 2 cells) became equal to that of normal rats.2' Recently surrounding and seemingly compressing a Bee has studied the effect of different lengths diminished number of type 1 cells.'4 Among ofhypoxic exposure on the ventilatory response the sustentacular cells were numerous nerve to hypoxia in rats.22 She reasoned that, during fibres which at times resembled a neuroma; the the cell division period, dopamine would not appearance was similar to that seen when nerves be synthesised. The response to hypoxia was are cut and subsequently "seek" the cells with enhanced in the first few days of exposure, then which they should synapse. The type 1 cells became normal after seven days, and "blunted" were of several types, thought to be of different after two weeks as previously shown.62' Do- functional or developmental significance, pamine inhibition is therefore one potential whereas in rats they are uniform. One might cause of blunting. Other workers, using differ- say that the organ looked "worn out". A similar ent species, made different suggestions - for S16 Barer example, central nervous system inhibition,23 The hypertensive rats were, however, hyper-

efferent inhibitory impulses in the carotid ventilating; at any partial pressure of oxygen Thorax: first published as 10.1136/thx.49.Suppl.S14 on 1 September 1994. Downloaded from nerve.24 Several potential causes of modulation they breathed more than their normo- of the ventilatory function of the carotid body tensive cousins and had a relative hypocapnia are thus emerging from animal studies; it may (figure).29 The line relating ventilation to oxy- become possible to test some of them in gen tension was parallel to that of controls, so humans. there was no increase in sensitivity to hypoxia. They also had severe disease in small carotid body arterioles with obstruction of the lumens. Carotid body, lung volume, and Unlike chronically hypoxic rats, they had a bronchoconstriction in hypoxia reduced number oftype 1 cells and diminished In hypoxic lung disease the residual volume is vascular volume rather than engorgement. The high and there is bronchoconstriction. Animal dopamine content of the carotid body was experiments have shown that carotid body re- normal but the noradrenaline content was in- flexes may contribute to these changes.2526 creased. The results could be explained if oxy- gen tension at the site of the oxygen sensor was reduced due to diminished blood flow and to Carotid body and systemic hypertension the high metabolism of this organ. The Milan in man, rat, and rabbit strain of hypertensive rat, currently being stud- In the late 1 970s a connection was noted ied in Sheffield, is different again. There is between the carotid body and systemic severe hypertension, the carotid body is smaller hypertension. Przybylski observed that spon- than in normotensive controls, and there is no taneously hypertensive rats of the Okamotu hyperventilation.30 Vascular changes are smaller strain hyperventilated.2" Then in Warsaw, Liv- than in New Zealand rats and the ventilatory erpool, and the German Democratic Republic response to graded hypoxia differs; a steeper separate groups found that the carotid bodies relation between ventilation and oxygen tension of this strain were larger than those of normal suggests increased sensitivity to hypoxia, an rats of a different strain;5 this result was con- observation also made in the Okamotu strain.3' firmed later with genetically similar nor- Habeck et al found the carotid bodies of motensive rats. Young men with borderline Lyon hypertensive rats to be larger than one hypertension were found to hyperventilate and strain but similar to a second normotensive had signs of peripheral chemoreceptor hyper- strain." In F, and F2 hybrids from the Okamotu activity," so it was proposed that carotid strain they found no relation between size and body overactivity might actually cause hyper- vascular or ventilatory changes.33 Angell-James tension. Later work in rats showed that et al3435 found no carotid body hypertrophy or enlargement of the carotid body occurred after ventilatory abnormalities in rabbits in whom

hypertension had developed; it seemed to be carotid vessels were narrowed by athero- http://thorax.bmj.com/ secondary to vascular disease in the supplying sclerosis or in rabbits with renal hyper- arteries."' The idea developed that carotid tension, nor was severe vascular disease in body overactivity was caused by ischaemia sec- renal hypertensive rats associated with carotid ondary to vascular obstruction. Several groups body enlargement.36 including that of Professor Heath (who had The link between carotid body size and func- shown the first link between carotid body tion in systemic hypertension is therefore un- weight and left ventricular weight) found en- resolved. Neither in man, rat, nor rabbit is larged carotid bodies in hypertensive patients enlargement always present; animal work sug- at necropsy; all showed vascular disease in gests that genetic differences may also affect on September 27, 2021 by guest. Protected copyright. carotid body vessels. The Liverpool group size. Where hyperventilation attributable to the made the surprising observation that these ca- carotid body has been found, the consensus rotid bodies closely resembled those ofpatients seems to be that it is secondary to restriction dying of hypoxic lung disease. Both showed of the blood supply. The reduced number of diminished numbers of type 1 cells and an type 1 cells in the New Zealand strain, com- overgrowth of sustentacular cells.'4 Again, pared with the increased number in chronically therefore, despite carotid body enlargement hypoxic rats, raises the question as to whether and functional changes in both rat and man, the type 1 cell population gives rise to over- closer study revealed differences between them. activity or underactivity of the carotid body. In More extensive studies in both humans and the New Zealand hypertensive rats the carotid animals have shown that high blood pressure is body was apparently responding normally or not invariably associated with enlargement nor, excessively to hypoxia, whereas the chronically in rats, with hyperventilation. hypoxic rats were under-responding. More- Habeck showed that some relatively young over, in hypoxic rats the dopamine content was hypertensive humans do not have large carotid increased whereas in the hypertensive rats it bodies and neither do patients dying from renal was normal. It is tempting to speculate that the hypertension, despite severe arterial disease in difference is related to the inhibiting effect of their carotid bodies.'5 In rats, too, there were the dopamine-containing type 1 cells. discrepancies. In Sheffield we studied the New Zealand strain of hypertensive rat for which genetically similar "normotensive" rats were Carotid body and renal function, available.29 The carotid bodies ofnormotensive especially in hypoxia and hypertensive individuals were similar in Hypoxia is associated with disturbances offluid size, though larger than those of other strains. balance and oedema, both on mountains and Carotid bodies in animal models of human disease: what do they teach us? S17 in hypoxic cor pulmonale. Climbers to very to hypoxia. Several groups have looked for

high altitudes are prone to pulmonary (and morphological changes in the carotid body but Thorax: first published as 10.1136/thx.49.Suppl.S14 on 1 September 1994. Downloaded from cerebral) oedema, and high altitude dwellers no clear picture has emerged. Naeye et al43 are subject to chronic mountain sickness with described abnormalities of the carotid body in oedema. The oedematous episodes of chronic a large series of cases, but Dinsdale et al44 and cor pulmonale were long considered to be several other groups could find no consistent caused by right heart failure, although the changes, although Cole et al described a re- moderate pulmonary hypertension and well duction in the numbers of type 1 cells and sustained cardiac output did not fit this dense-cored vesicles.5 It is a major problem explanation. In 1956 Stuart-Harris and col- to find suitable "controls". Perrin found sig- leagues in Sheffield showed that these patients nificantly raised dopamine and noradrenaline have an unexplained low renal blood flow.37 In levels in the carotid bodies of 13 cases ofsudden Sheffield it has long been considered that the infant death syndrome compared with age oedema might be caused by a disturbance of matched controls.45 In two of three cases of hormones which control fluid balance. Re- sudden infant death syndrome Heath et al cently Anand et al38 have found that healthy found proliferation of the "dark" chief cell soldiers stationed at very high altitudes for variant, while the third showed gross sus- many weeks have reduced renal blood flow, tentacular cell overgrowth and areas where sodium and water retention, various hormonal chief cells were almost absent; both these changes, and ankle oedema, together with evid- changes are seen in hypoxaemia.46 Can animal ence of right ventricular preponderance and "models" help us with this problem? It is known raised pulmonary artery pressure. These men, from work on lambs that the peripheral engaged in heavy exercise, were certainly not chemoreceptor apparatus is fully developed but in cardiac failure. The similarity between their not functional in the preterm fetus; it comes fluid balance and renal changes and those of into action after birth and must, therefore, have patients with hypoxic cor pulmonale, despite been suppressed. Our chronically hypoxic rats vigorous health on the one hand and severe have taught us that the hypoxic ventilatory illness on the other, supports a hormonal ex- response is variable. It is enhanced after short planation. term hypoxia but "blunted" after longer ex- A link between hypoxia and the carotid body posure, associated with an increased dopamine has only recently been detected in fluid balance content in the carotid body. In Sheffield Bee problems. Honig,28 reviewing observations et al47 are looking at newborn rabbits to see made both in man and animals, concluded that whether there is a time when the response to moderate hypoxia was associated with diuresis hypoxia is depressed which might correspond and natriuresis, whereas more severe hypoxia to the peak danger period for sudden infant was associated with water and sodium re- death syndrome in babies. The ventilatory re-

tention. In experiments on cats his group found sponse to hypoxia was tested in 10 awake rabbit http://thorax.bmj.com/ that hypoxia limited to the carotid body/ pups from week 1 to week 8 after birth. They sinus regions caused reflex diuresis and natri- fell into two groups. In five pups there was a uresis.28 The efferent limb of this reflex ap- profound depression of the response at about peared to be due to an increase or decrease of five weeks, while in the other five there were an unidentified bloodborne factor, a hormone; two troughs at about two and seven weeks. it was not dependent on renal nerves and there This work not only provides an illuminating was no reduction in renal blood flow. Almitrine, analogy with human babies, but it may indicate a which effect of drug mimics the hypoxia genetic variation. on September 27, 2021 by guest. Protected copyright. on the carotid body, also caused diuresis and natriuresis in cats." Karim and colleagues found that severe hypoxia in dogs caused a Conclusions reduction in renal blood flow and sodium re- Have these animal "models" taught us anything tention due to increased activity in the renal useful? Yes, I believe they have. We have learnt sympathetic nerves.40 In Sheffield it was shown that the carotid body is an active organ which in rats that small doses of almitrine caused changes, grows, and regresses with the events diuresis and natriuresis without change in renal of life. Moreover, its functional properties are blood flow; section of the carotid nerve ab- also variable. They have afforded us new ideas olished the response and it survived in a trans- which may help to solve human problems. Yet planted, denervated kidney.4 42 So far we have human studies warn us to be careful because been unable to cause sodium retention in there may be species differences and both an- chronically hypoxic rats so we do not yet have imal and human studies suggest that there may an animal "model" ofhuman hypoxic oedema, be genetic differences within a species. Above but the experiments just described open up all, the interaction between physiologists and new possibilities to be explored. pathologists has been most fruitful. Long may this continue. 1 Arias-Stella J. Human carotid body at high altitude. Carotid body in sudden infant death Abstracts of American Association of Pathology and Bacteriology, San Francisco, 1969. syndrome 2 Edwards C, Heath D, Harris P. The carotid body in myo- The sudden infant death syndrome (cot death) cardial hypertrophy and pulmonary emphysema; Barer have causes but a GR, Cook C, Glegg EJ, Shaw JW. Pulmonary vascular may many there is clear link and cardiac changes in rats and mice. Jf Pathol 1970, 101: with previous long periods of sleep apnoea. A Pi-iii. failure of 3 Heath D, Edwards C, Harris P. Post-mortem size and respiratory control has long been structure of the human carotid body. Thorax 1970;25: suspected, especially the carotid body response 129-40. S18 Barer

4 Edwards C, Heath D, Harris P. The carotid body in em- control of renal function and body fluid volumes in acute physema and left ventricular hypertrophy. Pathol 1971; arterial hypoxia. In: Acker H, O'Regan RG, eds. Physiology 104:1-13. of peripheral arterial chemoreceptors. Amsterdam: Elsevier, Thorax: first published as 10.1136/thx.49.Suppl.S14 on 1 September 1994. Downloaded from 5 Heath D, Smith P. Diseases ofthe human carotid body. London: 1983:395-429. Springer-Verlag, 1992. 29 Bee D, Barer G, Wach R, Pallot D, Emery C, Jones S. 6 Barer GR, Edwards C, Jolly AI. Changes in the carotid Structure and function of the carotid body in New Zealand body and ventilatory responses to hypoxia in chronically genetically hypertensive rats. Q Jf Exp Physiol 1989;74: hypoxic rats. Clin Sci 1976;50:311-3. 691-701. 7 Herget J, Brown CA, Skutilek S, Barer GR, Palecek F. 30 Brown C, Bee D. 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New York: Plenum Press, 1990: ilation and infant birth weight at 4300 J Appl 1986;60:1401-6. 357-62. 10 Flenley D, Franklin D, Millar J. The hypoxic drive to 33 Habeck J-O, Tafil-Klawe M, Klawe J. The carotid bodies breathing in chronic bronchitis and emphysema. Clin Sci of hypertensive/normotensive hybrid rats. Biomed Biochim 1970;38:503-18. Acta 1987;46:903-6. 11 Dhillon DP, Barer GR, Walsh M. The enlarged carotid 34 Angell-James JE, Clarke JA, de Burgh Daly M, Taton A. body of the chronically hypoxic and hypercapnic rat: a Respiratory and cardiovascular responses to hyperoxia, morphometric analysis. Q Jf Exp Physiol 1984;69:301-17. hypoxia and hypercapnia in the renal hypertensive rabbit: 12 Bee D, Pallot DJ, Barer GR. Division of type 1 and en- role of carotid body chemoreceptors. Jf Hypertens 1985;3: dothelial cells in the hypoxic rat carotid body. Acta Anat 213-23. 1986;126:226-9. 35 Angell-James JE, Clarke JA, de Burgh Daly M, Taton A. 13 Pallot DJ, Bee D, Barer GR, Jacob S. Some effects of Carotid chemoreceptor function and structure in the chronic stimulation on the rat carotid body. In: Eyzaguirre atherosclerotic rabbit: respiratory and cardiovascular C, Fidone SJ, Fitzgerald RS, Lahiri S, McDonald DM, responses to hyperoxia, hypoxia and hypercapnia. Car- eds. Arterial chemoreception. New York: Springer-Verlag, diovasc Res 1989;6:541-53. 1990. 36 Habeck J-O, Kreher C, Huckstorf C, Behm R. The carotid 14 Heath D, Smith P, Jago R. Hyperplasia of the carotid body. bodies of renal hypertensive rats. Anat Anz 1987;163: Pathol 1982;138:115-27. 49-55. 15 Habeck J-O. Morphological findings at the carotid bodies 37 Stuart-Harris CH, McKinnon J, Hammond JDS, Smith of humans suffering from different types of systemic WD. The renal circulation in chronic pulmonary disease hypertension or severe lung diseases. AnatAnz 1986;162: and heart failure. Q Jf Med 1956;25:389-405. 17-27. 38 Anand IS, Chandrashekhar Y, Rao SK, Malhotra RM, 16 Hurst G, Heath D, Smith P. 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The effect of short-term hypoxic exposure on vent- function and the response to renal denervation and ilation and carotid body dopamine blockade in an- ficiency of antidiuretic hormone. Biomed Biochim Acta aesthetized rats. Physiol 199 1;438:29P. 1991;50: 175-82. 23 Tenney SM, Ou LC. Hypoxic ventilatory response of cats 43 Naeye RL, Fisher RP, Ryser M, Whalen P. Carotid body at high altitude, an interpretation ofblunting. RespirPhysiol in the sudden infant death syndrome. Science 1976;191: 1977;30:185-99. 567-9. 24 Lahari SN, Smatresk KM, Porkorski M, Barnard P, Mokashi 44 Dinsdale F, Emery JL, Gadsdon DR. The carotid body - a A. Efferent inhibition of carotid chemoreception in chron- quantitative assessment in children. Histopathology 1977; ically hypoxic cats. Am Physiol 1983;245:R678-R683. 1:179-87. on September 27, 2021 by guest. Protected copyright. 25 Barer GR, Herget J, Sloan PJM, Suggett AJ. 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