J. fLmw.
PATH.
1978. \'0~.88.
PATHOLOGY ‘THE DOG
275
OF ACUTE ASSOCIATED
RESPIRATORY WITH PARAQUAT
DISTRESS POISOXIXG
IS
B) D.
F.
D.
KELLY',
H.
G.
P. G. G. DARKE, Al. Q. WEAVER
MORGAX,
and B.
PEARSON
C:.
GIBBS,
De@rtment of Patholqg, The Medical School, ~nioersi~v of Bristol. and the Departments of Veterimq Medicine and Veterina~~~ Surgery, School of Veterinary Science. Cnirwsi@ of Bristol, Bristol. L-.K:
ISTRODUCTION
The toxicity of paraquat for man and animals is notv well recognized and there have been more than 200 human cases of poisoning by this \\ccdkillci bet\z.ecn 1963 and 1974 (Anon, 1974). K nowledge of the morbid anatomy of paraquat poisoning has been obtained mainly from autopsy studies on fatal human cases (Almog and Thal, 1967; Bullivant, 1966; Campbell, 1968; Fennelly, Gallagher and Carroll, 1968; Hargreave, Gresham and Karayannopoulos, 1969; hiatthew, Logan, \Yoodruff and Heard, 1968; Oreopoulos. Soyann\vo, Sinniah, Fenton, hLlcGeown and Bruce, 1968; Smith and Heath. 1974; but the ultrastructural changes have been described in a lung biops!from a single human case of paraquat poisoning (Toner, Vctters, Spilg and Harland, 1970). 1lost of the information on the lesions produced in animal:, as a result of paraquat poisoning has so far been obtained from experiments on 1971; Clark, 3,IcElligott and Hurst, the small laboratory species (Brooks, 1966; hlurray and Gibson, 1972; Smith, Heath and Kay, 197-l; Vijeyaratnam and (:orrin, 197 1). This paper describes the pulmonary and other lesions foui~cl in dogs Lvith acute respiratory distress, in which paraquat was hclievcd to IN* the
c;IIIse. MATERIALS
AND
METHODS
Do,og 7. Electron micrograph fibroblast (f) is surrounded within alveolar lumen (alci. 16. l>og 7. Electron micrograph bodies adjacent to a fibroblast
F.
KELLY
et Ul.
of lung showing extensive intra-alveolar fibrosis. by crenated bascmrnt membrane. Other fibroblasts :: 13 950. of. lung showing numerous pleomorphic osmiophilic and between collagen fibrils. .: 21 000.
An (arrow
active r3, arc C:I lcified
I ‘eribronchiolar alveoli in dog 7 were lined by a continuous, single or dcxlble layI :r of cuboidal epithelial cells. The luminal plasma membranes of these cells forx ned short microvilli and the cell cytoplasm contained lipid, mitochon dria, of glycogen grar Riles. rou gh cndoplasmic reticulum and small accumulations
CANINE
RESPIRATORY
DISTRESS
287
\\‘ell developed junctional complexes were formed in the lateral plasma mcmbrane betlveen adjacent cells but distinct, lamellated osmiophilic bodies wrc not sc: 150.
Fig. 22. Dog HE.
7. A large epicardial :. 1.50.
coronary
artery
with segmental
fibrinoid
necrosis
ofthe
tunica
media.
290
D.
F.
KELLY
et
al.
DISCUSSIOX
Although a positive identification of paraquat was made in only 4 of the 10 dogs with respiratory distress, several features strongly suggest that this poison was responsible for the development of the signs in each case. These features were first, that the clinical course was similar in each case with vomiting followed by increasing respiratory distress; second, that the respiratory distress was more rapid in onset and severe than that seen in lung diseases which are known to occur in dogs and with which we are familiar; third, that there vvere no radiographic changes compatible with the degree of dyspnoea and fourth, that the lesions in the lungs, kidneys and adrenals were similar to those recognized in other species poisoned by paraquat (Clark et al., 1966). For these reasons, discussed in detail elsewhere, the following discussion is based on the assumption that the respiratory distress was a sequel to ingestion of paraquat (Darke et al., 1977). The histopathological and ultrastructural changes described here clearly account for the severe respiratory distress observed clinically. Both the acute haemorrhagic and necrotizing lesions seen in the early stages, and the regenerative epithelial and fibroblastic responses of the later phases of the condition would have seriously interfered with normal gaseous interchange at the alveolar level. Thus, the extensive loss of both type I and type II pneumonocytes would appear to be a major contributory factor in the early stages of respiratory distress, for it is well established from experimental studies (Cambar and Aviado, 1970; Fisher and Clements, 1969; Manktelovs, 1967; Robertson, Grossman and Ivemark, 1976) that loss of the latter cell type in particular, results in reduced surfactant synthesis and secretion which, in turn, leads to increased intra-alveolar surface tension, pulmonary oedema and alveolar collapse. Likewise in man (Toner et al., 1970) and rats (Robertson et al., 1976; Vijeyaratnam and Corrin, 1971) alveolar cell loss was seen to be the principal lung lesion during the early stages of poisoning with paraquat. In the latter species, loss of alveolar epithelial cells was observed as early as 3 days after the administration of paraquat at 25 mg per kg of body weight. Widespread pulmonary haemorrhage was undoubtedly an additional factor in the causation of acute respiratory failure but the absence of any underlying structural defect in alveolar capillary endothelium is puzzling. A similar situation has been described in rats (Vijeyaratnam and Corrin, 1971) where it was concluded that the development of both pulmonary haemorrhage and oedema reflected an increased permeability of capillary endothelial cells, although such a change was not detectable at the ultrastructural level. The failure to detect an endothelial lesion is also consistent with the observations of Sykes, Purchase and Smith ( 1977). In discussing the pathogenesis of these pulmonary lesions, it is relevant to consider the possibility that the damage is partly related to therapeutic oxygen adminstration. Retrospective examination of the regimes of oxygen therapy given to some of these dogs (Darke et al., 1977) suggests that it is unlikely that oxygen toxicity plays any significant part in the alveolar damage. Comparison
CANINE
RESPIRATORY
DISTRESS
2!ll
of the lungs of oxygen-treated dogs with those of dogs to which oxygen was not given showed no significant differences in the extent or severity of the pulmonar) lesions. Referring to the active proliferation of alveolar fibroblasts and epithelial cells during the later stages of the condition, it is reasonable to conclude that such a response, although perhaps reparative in nature, would have contributed significantly to the progressively w0rsenin.g state of dyspnoea observed clinicall!, in these dogs. For, besides partially obliterating alveolar spaces, the deeper infiltration of alveolar septa by rapidly dividing fihroblasts and the ensuing interstitial fibrosis would present an increasingly impervious barrier to normal gaseous exchange. It is significant, therefore, that alveolar fibrosis occurred as early as 2 days from the onset of clinical signs, and became more widespread in parallel with the development of respiratory distress, particularly in those dogs which survived for longer periods of time. The proliferati1.e response of bronchiolar epithelial cells was at first reminiscent of that seen in dogs infected with adenovirus (Kelly, 1969; Wright, Thompson and Cornwell, 1971) and \vas assumed, on this basis, to account for theepithelializationof peribron.chiolal alveoli 1~): direct extension locally. It has been show:n recently, however, that regeneration of type II cells can occur de nova in the alveoli of dogs previousl! exposed to X-nitroso X-methyl urethane and it is of interest that these alveolar, cells. in an immature state of differentiation (Ryan, Bell and Barrett, 1976 bore a close ultrastructural resemblance to those seen in the lungs of the dogs described in this paper. Thus, in both cases the cells contain.ed distinct aggregatcx of glycogen and possessed short microvilli but lacked the characteristic, lamcbllated, osmiophilic bodies of the mature surfactant-producing type 11 cells. Despite the absence of this latter characteristic, however, the finding 01‘ such morphologically similar cells in the early regenerative phases of al\reolar injury produced by N-n.itroso &-methyl urethane and in our dogs, supports the \-iew that these are immature type 11 cells. The significance of the extra-pulmon.ary lesions in relation to the overall clinical signs presented by this series of dogs is difficult to assess but necrosis of the adrenocortical zona glomerulosa is distinctly unusual and does not occur spontaneously in the dog. A similar change has been described in experimental paraquat poisoning of mice (Clark et al., 1966) but does not appear to be ;I commonly recognized feature of paraquat poisoning in other species. It is of interest that comparable adrenocorticolytic activity is shown by the chemicall) similar compound o,p’DDD* [l, 1 dichloro-2(o-chlorophenyl)-2-i’p-chlorophenyljethane], which is used therapeutically in the treatment of clinical hypcxradrenocorticalism (Schechter, Stabenfeldt, Gribble and Ling, 1973), although a point of difference is that all the isomers of this compound exert their effect on the zonae fasciculata-reticularis and do not affect the zone glomerulosa (Hart, Reagan and Adamson, 1973). It seems likely that this effect of paraquat is dore-related since the most striking adrenocortical necrosis was seen in dog 1 which had a short, rapidly fatal illness lasting less than 24 11 iDarke et al., 1977). Other dogs in this series had only focal cell necrosis * “Lysodren”.
Calbiochem,
La Jolla,
California.
292
D.
F.
KELLY
et
cd.
accompanied by evidence of regeneration, suggesting that the adrenal lesion is unlikely to contribute significantly to the functional effects of paraquat poisoning. The finding of renal tubular necrosis in the present investigation is in line with earlier studies on the toxic effects of paraquat in dogs and certainly in our dogs was related to the clinical signs of renal failure (Darke et al., 1977). It appears that the ability to produce renal tubular damage is a universal property of paraquat in a wide variety of species including rats, mice, guinea pigs, monkeys (Clark et al., 1966; Fowler and Brooks, 197 1; Murray and Gibson, 1972) and also in man, in whom anuric renal failure may develop (Anon, 1976; Oreopoulo; et al., 1968). The striking coronary arterial medial necrosis seen in our dogs, on the other hand, has not hitherto been recognized in any species in association with paraquat poisoning. AloreoT’er, the histological appearances of these lesions in x-essels of varying size are quite distinct from those commonly encountered in the aged dog m lvhich a non-necrotizing, non-inflammatory, intimal hyalinosis is seen confined to the small, intramural coronary arteries (Detweiler, Luginbiihl, Buchanan and Patterson, 1968; Luginbiihl and Detweiler? 1965). Thrombosis of affected vessels was not seen but it is likely that the focal myocardial necrosis is a sequel to altered coronary perfusion, if not by- vascular occlusion then possibly as a result of vasospasm. In man, clectrccardiographic abnormalities attributable to toxic myccarditis have been described in paraquat poisoning but lvere not substantiated by pathological esaminaticn (Rullivant, 1968). The finding of unequivocal pathological lesions in both the myccardium and coronarv arteries of the piacsent srries of dogs suggests that fLIrther electrocardiographic investigations in this species lvould be worthn-hile to determine the significance of cardiac dysfunction in relation to the invariably fatal efEcts of paraquat poisoning.
The morbid anatomical, histclogical and ultrastructural changes in the lungs of 10 dogs with acute respiratory distress are described. The duration of signs varied from 12 h to 7 days. The early phase of respirator!distress was associated with pulmonary haemorrhage and oedema, focal necrosis of bronchiolar epithelium, alveolar collapse and loss of both type I and type II pneumonocytes. In the later stages there Lvas intra-alveolar fibrosis: bronchiolar epithelial regeneration and alveolar epithelialization by immature type II pneumonocytes. Paraquat was recovered from 4 of the dogs and the similarity betM-een the clinical and pathological features Lvithin the group, and to paraquat that this compound was probably poisoning in other species, suggested responsible for the lesions in all 10 dogs. Histological changes also included necrosis of the adrenal zona glomerulosa, renal tubular necrosis, focal myocardial necrosis and medial fibrinoid necrosis a change not hitherto described in association with of coronary arteries, paraquat poisoning. The lesions are discussed in relation to their possible functional role in the development of clinical signs, and are compared with the
CANINE
lesions of paraquat animals.
poisoning
RESPIRATORY
which
2%
DISTRESS
have been described
in man and laborator>
XCliNOWLEDGMENTS
\Vr arc‘ grateful to C:. C:. ,Jcal and cjaph)- and c‘lrctron microscopy.
C%ristine
Lambcrt
Tar a&tancc
\vitll
!)IIOIII-
REFERENCES
.\IIIIo~, (ill., and Tal, E. (1967). Death from parltquat alicr yubcutancous injt,ctic)ll. British AUedical 3ozmn1, 3, 72 1. .4nonymous (1974). The paraquat puzzle. Llledical jGzmt7l qf hstr.cllitr. 2, NC). .Inonymous (1976). Paraquat poisoning. Lntzef, i, 1057. B~~~oks. R. E. ( 1971). Ultrastructure of lung lesions produced by ingchtvd c~ll~~ulic:al\. 1. Effect nf the herbicide paraquat on mouse lung. Lnhoratq~ /ux\/i~n/ion. 35, 5:s 535. Bllllivant. C:. M. (1966). Accidental poisonin? by paraquat : rt’port of two I’.*\Y~ ill man. flrilish ~\~edical3ournal~ 1, 1272-1275. ~~an~l~;~r, 1’. .J., and .-\viado, D. 11. (1970). B ~onchopulmonary 1 ctirt.t~ of p;ii‘a(/“:t~ and expectorants. drchi;Je.r of Enoironmerzfnl Health, 20, WS19+. (‘an~pl~c~ll. S. (1968). Death from paraquat in a child. Larirp/. i, IN. (Clark. 1~. C.. McElligott. T. F.. and Hurst. E. W. (1966i. The toxicity of palaqua,r. British 3ournal ~f‘lndustrial L21edicine, 23, 126-l 32. I)arke. I’. G. t‘ in rlcctron microscopy. Journal of Cell BioloD. 27, 1371\. &Ii)-. 1.~. F. (1969). C:anine proliferative and necrotizing trachcobronchitis will1 intranuclear inclusion-body and hyaline memhranr formation. Pntholqiu LPterinaria, 6, 227-234. Luginbiihl, H., and Detweiler, D. K. (1965). c’,ar d iovascular lesions in dogs. .-l/lrlni.~ oj” the .Mez! York Acudenly of Sciences, 127, 5 17-540. I\Ianktclow, B. W. (1967). The loss of pulmonary surfactant in paraquat poisoning: a model for the study of the respiratory distress syndrome. Briti.rh Journal o/ Experimental Pathology, 48, 366-369. hlatthew, H.. Logan, A., Woodruff, M. F. A., and Heard, B. (1968). Paraqllat poisoning--lung transplantation. Brifish MedicalJournal. 3, 759.-763.
294
D.
F.
KELLY
et
cd.
Murray, R. E., and Gibson, J. E. (1972). A comparative study of paraquat intoxication in rats, guinea pigs and monkeys. Exterimental and Molecular Pathology, 17, 3 17-325. Qreopoulos, D. G., Soyannwo, M. A. O., Sinniah, R., Fenton, S. S. A., McGeown, M. G., and Bruce, J. H. ( 1968). Acute renal failure in case of paraquat poisoning. British Medical Journal, 1, 749-750. Robertson, B., Grossman, G., and Ivemark, B. (1976). The alveolar lining layer in experimental paraquat poisoning. Acta pathologica et microbiologica scandinauica, Section A, 84, 40-46. Ryan, S. F., Bell, A. L. L., and Barrett, C. R. (1976). Experimental acute alveolar injury in the dog. Morphologic-mechanical correlations. American Journal of Pathology, 82, 353-364. Schechter, R. D., Stabenfeldt, G. H., Gribble, D. H., and Ling, G. V. (1973). Treatment of Cushing’s Syndrome in the dog with an adrenocorticolytic agent (o,plDDD). Journal of the American Veterinary Medical Association, 162, 629-639. Smith, P., and Heath, D. (1974). Paraquat lung: a reappraisal. Thorax, 29,643-653. Smith, P., Heath, D., and Kay, J. M. (1974). The pathogenesis and structure of paraquat-induced pulmonary fibrosis in rats. Journal of Pathology, 114, 57-67. Sykes, B. I., Purchase, I. F. H., and Smith, L. L. (1977). Pulmonary ultrastructure after oral and intravenous dosage of paraquat to rats. Journal of Pathology, 121, 233-241. Toner, P. G., Vetters, J. M., Spilg, W. G. S.: and Harland, W. A. (1970). Fine structure of the lung lesion in a case of paraquat poisoning. Journal of Pathology, 102, 1822185. Vijeyaratnam, G. S., and Corrin, B. (1971). Experimental paraquat poisoning: a histological and electron-optical study of the changes in the lung. Journal oj‘ Pathology, 103, 123-l 29. Wright, N. G., Thompson, H., Cornwell, H. J. C. (1971). Canine adenovirus pneumonia. Research in Veterinary Science, 12, 162-167. [Receitled for publication,
June 24th, 19771
PATH.
1978. \'0~.88.
PATHOLOGY ‘THE DOG
275
OF ACUTE ASSOCIATED
RESPIRATORY WITH PARAQUAT
DISTRESS POISOXIXG
IS
B) D.
F.
D.
KELLY',
H.
G.
P. G. G. DARKE, Al. Q. WEAVER
MORGAX,
and B.
PEARSON
C:.
GIBBS,
De@rtment of Patholqg, The Medical School, ~nioersi~v of Bristol. and the Departments of Veterimq Medicine and Veterina~~~ Surgery, School of Veterinary Science. Cnirwsi@ of Bristol, Bristol. L-.K:
ISTRODUCTION
The toxicity of paraquat for man and animals is notv well recognized and there have been more than 200 human cases of poisoning by this \\ccdkillci bet\z.ecn 1963 and 1974 (Anon, 1974). K nowledge of the morbid anatomy of paraquat poisoning has been obtained mainly from autopsy studies on fatal human cases (Almog and Thal, 1967; Bullivant, 1966; Campbell, 1968; Fennelly, Gallagher and Carroll, 1968; Hargreave, Gresham and Karayannopoulos, 1969; hiatthew, Logan, \Yoodruff and Heard, 1968; Oreopoulos. Soyann\vo, Sinniah, Fenton, hLlcGeown and Bruce, 1968; Smith and Heath. 1974; but the ultrastructural changes have been described in a lung biops!from a single human case of paraquat poisoning (Toner, Vctters, Spilg and Harland, 1970). 1lost of the information on the lesions produced in animal:, as a result of paraquat poisoning has so far been obtained from experiments on 1971; Clark, 3,IcElligott and Hurst, the small laboratory species (Brooks, 1966; hlurray and Gibson, 1972; Smith, Heath and Kay, 197-l; Vijeyaratnam and (:orrin, 197 1). This paper describes the pulmonary and other lesions foui~cl in dogs Lvith acute respiratory distress, in which paraquat was hclievcd to IN* the
c;IIIse. MATERIALS
AND
METHODS
Do,og 7. Electron micrograph fibroblast (f) is surrounded within alveolar lumen (alci. 16. l>og 7. Electron micrograph bodies adjacent to a fibroblast
F.
KELLY
et Ul.
of lung showing extensive intra-alveolar fibrosis. by crenated bascmrnt membrane. Other fibroblasts :: 13 950. of. lung showing numerous pleomorphic osmiophilic and between collagen fibrils. .: 21 000.
An (arrow
active r3, arc C:I lcified
I ‘eribronchiolar alveoli in dog 7 were lined by a continuous, single or dcxlble layI :r of cuboidal epithelial cells. The luminal plasma membranes of these cells forx ned short microvilli and the cell cytoplasm contained lipid, mitochon dria, of glycogen grar Riles. rou gh cndoplasmic reticulum and small accumulations
CANINE
RESPIRATORY
DISTRESS
287
\\‘ell developed junctional complexes were formed in the lateral plasma mcmbrane betlveen adjacent cells but distinct, lamellated osmiophilic bodies wrc not sc: 150.
Fig. 22. Dog HE.
7. A large epicardial :. 1.50.
coronary
artery
with segmental
fibrinoid
necrosis
ofthe
tunica
media.
290
D.
F.
KELLY
et
al.
DISCUSSIOX
Although a positive identification of paraquat was made in only 4 of the 10 dogs with respiratory distress, several features strongly suggest that this poison was responsible for the development of the signs in each case. These features were first, that the clinical course was similar in each case with vomiting followed by increasing respiratory distress; second, that the respiratory distress was more rapid in onset and severe than that seen in lung diseases which are known to occur in dogs and with which we are familiar; third, that there vvere no radiographic changes compatible with the degree of dyspnoea and fourth, that the lesions in the lungs, kidneys and adrenals were similar to those recognized in other species poisoned by paraquat (Clark et al., 1966). For these reasons, discussed in detail elsewhere, the following discussion is based on the assumption that the respiratory distress was a sequel to ingestion of paraquat (Darke et al., 1977). The histopathological and ultrastructural changes described here clearly account for the severe respiratory distress observed clinically. Both the acute haemorrhagic and necrotizing lesions seen in the early stages, and the regenerative epithelial and fibroblastic responses of the later phases of the condition would have seriously interfered with normal gaseous interchange at the alveolar level. Thus, the extensive loss of both type I and type II pneumonocytes would appear to be a major contributory factor in the early stages of respiratory distress, for it is well established from experimental studies (Cambar and Aviado, 1970; Fisher and Clements, 1969; Manktelovs, 1967; Robertson, Grossman and Ivemark, 1976) that loss of the latter cell type in particular, results in reduced surfactant synthesis and secretion which, in turn, leads to increased intra-alveolar surface tension, pulmonary oedema and alveolar collapse. Likewise in man (Toner et al., 1970) and rats (Robertson et al., 1976; Vijeyaratnam and Corrin, 1971) alveolar cell loss was seen to be the principal lung lesion during the early stages of poisoning with paraquat. In the latter species, loss of alveolar epithelial cells was observed as early as 3 days after the administration of paraquat at 25 mg per kg of body weight. Widespread pulmonary haemorrhage was undoubtedly an additional factor in the causation of acute respiratory failure but the absence of any underlying structural defect in alveolar capillary endothelium is puzzling. A similar situation has been described in rats (Vijeyaratnam and Corrin, 1971) where it was concluded that the development of both pulmonary haemorrhage and oedema reflected an increased permeability of capillary endothelial cells, although such a change was not detectable at the ultrastructural level. The failure to detect an endothelial lesion is also consistent with the observations of Sykes, Purchase and Smith ( 1977). In discussing the pathogenesis of these pulmonary lesions, it is relevant to consider the possibility that the damage is partly related to therapeutic oxygen adminstration. Retrospective examination of the regimes of oxygen therapy given to some of these dogs (Darke et al., 1977) suggests that it is unlikely that oxygen toxicity plays any significant part in the alveolar damage. Comparison
CANINE
RESPIRATORY
DISTRESS
2!ll
of the lungs of oxygen-treated dogs with those of dogs to which oxygen was not given showed no significant differences in the extent or severity of the pulmonar) lesions. Referring to the active proliferation of alveolar fibroblasts and epithelial cells during the later stages of the condition, it is reasonable to conclude that such a response, although perhaps reparative in nature, would have contributed significantly to the progressively w0rsenin.g state of dyspnoea observed clinicall!, in these dogs. For, besides partially obliterating alveolar spaces, the deeper infiltration of alveolar septa by rapidly dividing fihroblasts and the ensuing interstitial fibrosis would present an increasingly impervious barrier to normal gaseous exchange. It is significant, therefore, that alveolar fibrosis occurred as early as 2 days from the onset of clinical signs, and became more widespread in parallel with the development of respiratory distress, particularly in those dogs which survived for longer periods of time. The proliferati1.e response of bronchiolar epithelial cells was at first reminiscent of that seen in dogs infected with adenovirus (Kelly, 1969; Wright, Thompson and Cornwell, 1971) and \vas assumed, on this basis, to account for theepithelializationof peribron.chiolal alveoli 1~): direct extension locally. It has been show:n recently, however, that regeneration of type II cells can occur de nova in the alveoli of dogs previousl! exposed to X-nitroso X-methyl urethane and it is of interest that these alveolar, cells. in an immature state of differentiation (Ryan, Bell and Barrett, 1976 bore a close ultrastructural resemblance to those seen in the lungs of the dogs described in this paper. Thus, in both cases the cells contain.ed distinct aggregatcx of glycogen and possessed short microvilli but lacked the characteristic, lamcbllated, osmiophilic bodies of the mature surfactant-producing type 11 cells. Despite the absence of this latter characteristic, however, the finding 01‘ such morphologically similar cells in the early regenerative phases of al\reolar injury produced by N-n.itroso &-methyl urethane and in our dogs, supports the \-iew that these are immature type 11 cells. The significance of the extra-pulmon.ary lesions in relation to the overall clinical signs presented by this series of dogs is difficult to assess but necrosis of the adrenocortical zona glomerulosa is distinctly unusual and does not occur spontaneously in the dog. A similar change has been described in experimental paraquat poisoning of mice (Clark et al., 1966) but does not appear to be ;I commonly recognized feature of paraquat poisoning in other species. It is of interest that comparable adrenocorticolytic activity is shown by the chemicall) similar compound o,p’DDD* [l, 1 dichloro-2(o-chlorophenyl)-2-i’p-chlorophenyljethane], which is used therapeutically in the treatment of clinical hypcxradrenocorticalism (Schechter, Stabenfeldt, Gribble and Ling, 1973), although a point of difference is that all the isomers of this compound exert their effect on the zonae fasciculata-reticularis and do not affect the zone glomerulosa (Hart, Reagan and Adamson, 1973). It seems likely that this effect of paraquat is dore-related since the most striking adrenocortical necrosis was seen in dog 1 which had a short, rapidly fatal illness lasting less than 24 11 iDarke et al., 1977). Other dogs in this series had only focal cell necrosis * “Lysodren”.
Calbiochem,
La Jolla,
California.
292
D.
F.
KELLY
et
cd.
accompanied by evidence of regeneration, suggesting that the adrenal lesion is unlikely to contribute significantly to the functional effects of paraquat poisoning. The finding of renal tubular necrosis in the present investigation is in line with earlier studies on the toxic effects of paraquat in dogs and certainly in our dogs was related to the clinical signs of renal failure (Darke et al., 1977). It appears that the ability to produce renal tubular damage is a universal property of paraquat in a wide variety of species including rats, mice, guinea pigs, monkeys (Clark et al., 1966; Fowler and Brooks, 197 1; Murray and Gibson, 1972) and also in man, in whom anuric renal failure may develop (Anon, 1976; Oreopoulo; et al., 1968). The striking coronary arterial medial necrosis seen in our dogs, on the other hand, has not hitherto been recognized in any species in association with paraquat poisoning. AloreoT’er, the histological appearances of these lesions in x-essels of varying size are quite distinct from those commonly encountered in the aged dog m lvhich a non-necrotizing, non-inflammatory, intimal hyalinosis is seen confined to the small, intramural coronary arteries (Detweiler, Luginbiihl, Buchanan and Patterson, 1968; Luginbiihl and Detweiler? 1965). Thrombosis of affected vessels was not seen but it is likely that the focal myocardial necrosis is a sequel to altered coronary perfusion, if not by- vascular occlusion then possibly as a result of vasospasm. In man, clectrccardiographic abnormalities attributable to toxic myccarditis have been described in paraquat poisoning but lvere not substantiated by pathological esaminaticn (Rullivant, 1968). The finding of unequivocal pathological lesions in both the myccardium and coronarv arteries of the piacsent srries of dogs suggests that fLIrther electrocardiographic investigations in this species lvould be worthn-hile to determine the significance of cardiac dysfunction in relation to the invariably fatal efEcts of paraquat poisoning.
The morbid anatomical, histclogical and ultrastructural changes in the lungs of 10 dogs with acute respiratory distress are described. The duration of signs varied from 12 h to 7 days. The early phase of respirator!distress was associated with pulmonary haemorrhage and oedema, focal necrosis of bronchiolar epithelium, alveolar collapse and loss of both type I and type II pneumonocytes. In the later stages there Lvas intra-alveolar fibrosis: bronchiolar epithelial regeneration and alveolar epithelialization by immature type II pneumonocytes. Paraquat was recovered from 4 of the dogs and the similarity betM-een the clinical and pathological features Lvithin the group, and to paraquat that this compound was probably poisoning in other species, suggested responsible for the lesions in all 10 dogs. Histological changes also included necrosis of the adrenal zona glomerulosa, renal tubular necrosis, focal myocardial necrosis and medial fibrinoid necrosis a change not hitherto described in association with of coronary arteries, paraquat poisoning. The lesions are discussed in relation to their possible functional role in the development of clinical signs, and are compared with the
CANINE
lesions of paraquat animals.
poisoning
RESPIRATORY
which
2%
DISTRESS
have been described
in man and laborator>
XCliNOWLEDGMENTS
\Vr arc‘ grateful to C:. C:. ,Jcal and cjaph)- and c‘lrctron microscopy.
C%ristine
Lambcrt
Tar a&tancc
\vitll
!)IIOIII-
REFERENCES
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