A group of rats was born in and spent the first 4 weeks of life at a simulated altitude of 3550 m. Two animals were killed immediately afterwards and the remaining 16 were allowed to recover for various times up to a maximum of 12 weeks at sea-level atmospheric pressure. On ultrastructural examination, the pulmonary arterioles of hypoxic rats showed muscularization, the new layer of mature smooth muscle cells containing abundant organelles and myofilaments. These cells were bounded by prominent elastic laminae. During the recovery period, the medial layer became progressively thinned, but the cells still retained some characteristics of smooth muscle by 12 weeks' recovery. When a similar group of ten hypoxic rats was allowed to recover for 12 weeks before being given monocrotaline, there was early enlargement of the residual smooth muscle cells in the media of pulmonary arterioles and within 5 weeks there was again a thick layer of medial smooth muscle. This was in contrast to the sparse, weakly muscularized arterioles seen in eight similarly treated rats born under normoxic conditions. The relevance is discussed of these findings to the rare occurrence of primary pulmonary hypertension in people who were born at high altitude but returned to sea-level during childhood.

A group of Wistar rats was treated with two subcutaneous injections of monocrotaline, at 4 and 6 weeks of age. They were then killed 1 month after the initial injection. A second group of rats was born and reared in hypobaric hypoxia for 1 month before being killed. Both groups had age-matched controls. The ultrastructure of pulmonary arterioles from all groups was studied, and quantitative measurements were made of the volume densities of organelles within the cytoplasm of arteriolar smooth muscle cells. The pulmonary arterioles of rats treated with monocrotaline contained immature smooth muscle cells with coarse peripheral myofilaments and were bounded by thin indistinct elastic laminae. In contrast, the arteriolar smooth muscle cells of hypoxic rats were mature with fine myofilaments and bounded by electron dense laminae. When compared with both their respective controls and the alternative test group, the muscle cells from rats treated with monocrotaline had significantly lower volume densities of dense bodies, and the hypoxic muscle cells had significantly higher densities of mitochondria. The pulmonary arteriolar muscularization in rats would appear to be a nonuniform process producing smooth muscle cells with differing cytoplasmic features that suggest differing cellular functions.

The weights of the individual carotid bodies and cardiac ventricles were obtained at necropsy in five series of subjects. The first comprised 10 cases free of cardiopulmonary disease to act as controls. The second consisted of 10 cases of pulmonary emphysema. The third was composed of 8 cases characterized by sustained alveolar hypoxia due to causes other than pulmonary emphysema. The fourth comprised 10 cases of systemic hypertension or severe left ventricular failure. The fifth was made up of 10 cases of diseases of the liver or alimentary canal. The study confirmed that enlargement of the carotid bodies is common in cases of pulmonary emphysema or sustained alveolar hypoxia with right ventricular hypertrophy. It is also common in cases of systemic hypertension with left ventricular hypertrophy. It was also revealed that enlargement of the carotid bodies may occur in cirrhosis of the liver. We believe this to be the first report of that association.

BACKGROUND--Nodules of cells showing a striking histological similarity to those of arachnoid villi have previously been found closely adjacent to pulmonary venules in several diseases associated with alveolar hypoxia or pulmonary oedema including mitral stenosis, plexogenic pulmonary arteriopathy, pulmonary thromboembolism, and chronic obstructive pulmonary disease. METHODS--Histological sections of the lungs of seven adult native highlanders from La Paz (3600 m) were examined. RESULTS--Arachnoid nodules were found in the lungs of one Aymara and one Mestizo Indian. CONCLUSIONS--These bodies may have a similar function to that of arachnoid granulations which transfer excess cerebrospinal fluid to the dural venous sinuses. In the native highlanders it is possible that they contribute to the avoidance of excessive hydration of the interstitial tissue of the alveolar walls with return of fluid into the pulmonary venules, preventing incipient pulmonary oedema.

INTRODUCTION: There is evidence to suggest that life at high altitude causes changes in the population of pulmonary endocrine cells, possibly because of exposure to chronic hypoxia. A study was made of the populations of pulmonary endocrine cells in three Aymara Indians and three Mestizos of La Paz (3600 m), Bolivia, which were compared with those in four white lowlanders. METHODS: Pulmonary endocrine cells were immunolabelled for neurone specific enolase and their two major secretory products, gastrin releasing peptide and calcitonin, and their numbers expressed per cm2 of tissue section. RESULTS: No differences in morphology, number, content, or distribution of immunoreactive cells were found when the native highlanders were compared with the lowlanders. CONCLUSIONS: If chronic hypoxia as such exerts an influence on human pulmonary endocrine cells it was not apparent in this morphological study. There was no increase in gastrin releasing peptide containing pulmonary endocrine cells, such as have previously been seen in patients with pulmonary hypertension characterised by plexogenic pulmonary arteriopathy. This may be due to the fact that in plexogenic pulmonary arteriopathy there is free migration of smooth muscle cells. Although three of the highlanders in this present study showed pulmonary vascular remodelling, this was in contrast only modest.

The lungs from three cases of pulmonary emphysema obtained at heart-lung transplantation were examined by electron microscopy to determine the origin of intimal longitudinal muscle and the formation of muscular tubes in small pulmonary arteries and arterioles. The earliest change consisted of migration of mature smooth muscle cells from the media of small pulmonary arteries, through gaps in the internal elastic lamina, into the subendothelial space. Most of these cells then adopted a longitudinal orientation, maintained a muscular phenotype, and became enmeshed in a web of elastic fibres. A small minority, immediately subjacent to the endothelium, were orientated circularly and, in some vessels, were enclosed by rudimentary internal and external elastic laminae to form early muscular tubes. Pulmonary arterioles, which are normally devoid of a media, contained several layers of circularly orientated smooth muscle cells, some of which also formed muscular tubes. It is postulated that the limited migration of mature smooth muscle cells seen in states of chronic hypoxia is mediated by a different stimulus from that causing the florid invasion of the intima by immature smooth muscle, with subsequent transformation into myofibroblasts, which characterize plexogenic pulmonary arteriopathy.

Carotid bodies from 15 human fetuses of gestational ages 13-19 weeks were examined by light and electron microscopy. They were also labeled with antisera to methionine- and leucine-enkephalins, substance P, and bombesin. At 13 weeks of gestation most fetal glomic cells formed a homogeneous population but a few could be distinguished by light microscopy as rounded, pale fetal chief cells or elongated, darker fetal sustentacular cells, a distinction that became more certain with increasing gestational age. Electron microscopy confirmed this distinction, in which fetal chief cells contained dense-core vesicles and were partially enfolded by cytoplasmic extensions of fetal sustentacular cells. Immunoreactivity to methionine- and leucine-enkephalins was found at all gestational ages and was confined largely to fetal chief cells. Immunoreactivity to substance P was less specific, and there was no reaction for bombesin. Thus, by as early as the 13th week of gestation the two principal types of cell of the mature human carotid body begin to become recognizable on paraffin-embedded sections stained with hematoxylin and eosin. Furthermore, fetal chief cells can synthesize the peptides found in the adult.

The pulmonary circulation of the rat is widely used as an animal model for studies of human pulmonary hypertension. It is not difficult to understand its appeal. The species is a small laboratory animal which is readily accommodated in decompression chambers for studies for simulated high altitude. It is also very susceptible to the action of the metabolites of pyrrolizidine alkaloids which rapidly lead to severe pulmonary vascular disease in the absence of intrinsic heart and lung disease, thus suggesting its value as an animal model of primary pulmonary hypertension. However, these obvious advantages of the rat pulmonary circulation are outweighed by the fact that its pathological reactions to hypoxia and noxious dietary agents differ significantly from those found in human disease. This can lead to erroneous conclusions as to the nature of the remodelling of the human pulmonary vasculature in pulmonary hypertension.

HistopathologyVolume 19, Issue 6 p. 567-569 Pulmonary vasculature in Fabry's disease P. SMITH, P. SMITH Department of Pathology, University of Liverpool, UKSearch for more papers by this authorD. HEATH, D. HEATH Department of Pathology, University of Liverpool, UKSearch for more papers by this authorB. RODGERS, B. RODGERS Department of Pathology, University of Liverpool, UKSearch for more papers by this authorT. HELLIWELL, T. HELLIWELL Department of Pathology, University of Liverpool, UKSearch for more papers by this author P. SMITH, P. SMITH Department of Pathology, University of Liverpool, UKSearch for more papers by this authorD. HEATH, D. HEATH Department of Pathology, University of Liverpool, UKSearch for more papers by this authorB. RODGERS, B. RODGERS Department of Pathology, University of Liverpool, UKSearch for more papers by this authorT. HELLIWELL, T. HELLIWELL Department of Pathology, University of Liverpool, UKSearch for more papers by this author First published: December 1991 https://doi.org/10.1111/j.1365-2559.1991.tb01510.xCitations: 16AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Bagdade JD, Parker F., Ways PO, Morgan TE, Lagunoff D., Eidelman S.. Fabry's disease. A correlative clinical, morphologic and biochemical study. Lab. Invest. 1968; 18; 681–688. 2 Dawson DM, Miller DC, Kolodny EH, Halperin JJ et al. Fabry's disease (alpha-galactosidase A deficiency), with involvement of nervous system and blood vessels, with cerebral, myocardial, and renal infarcts. (Massachusetts General Hospital Case Records). N. Engl. J. Med. 1984; 310; 106–114. 3 Farge D., Nadler S., Wolfe LS, Barre P., Jothy S.. Diagnostic value of kidney biopsy in heterozygous Fabry's disease. Arch. Pathol. Lab. Med. 1985; 109; 85–88. 4 Gemignani F., Marbini A., Bragaglia MM, Govoni E.. Pathological study of the sural nerve in Fabry's disease. Eur. Neurol. 1984; 23; 173–181. 5 Roberts DH, Gilmore IT. Achalasia in Anderson-Fabry's disease. J. Roy. Soc. Med. 1984; 77; 430–431. 6 Rosenberg DM, Ferrans VJ, Fulmer JD et al. Chronic airflow obstruction in Fabry's disease. Am. J. Med. 1980; 68; 898–905. Citing Literature Volume19, Issue6December 1991Pages 567-569 ReferencesRelatedInformation

A group of Wistar albino rats was injected subcutaneously with monocrotaline to induce vasoconstrictive hypertensive pulmonary vascular disease characterized by medial hypertrophy of small pulmonary arteries, the appearance of muscular pulmonary arterial vessels of arteriolar dimensions (less than 20 μm in diameter), and exudative changes in the lung parenchyma. The vascular abnormalities were quantified by measuring the percentage medial thickness of small pulmonary arteries, the number of muscular pulmonary arterial vessels below 20 μm in diameter per cm 2 of lung section and by determining the smallest arterial vessels in each case showing muscularity. A second group of rats was born in a decompression chamber and kept in hypobaric hypoxia for a month of the neonatal period, developing hypoxic hypertensive pulmonary vascular disease as a consequence. The animals in this group were allowed to recover in room air for a period of 3 months and were then injected with the same dose of monocrotaline as that given to the first group. The rats previously exposed to hypoxia exhibited an exaggerated response to the alkaloid, showing in particular many more small muscular pulmonary arterial vessels which were of a smaller diameter than those found in the eupoxic rats treated with the alkaloid. The experiment demonstrates that perinatal hypoxia exaggerates the effects of agents inducing vasoconstrictive pulmonary hypertension with a shift of the segment of the pulmonary arterial tree involved to the periphery as in hypoxia. Reports of a similar phenomenon are noted as occurring in babies born at high altitude, spending their infancy there and subsequently developing primary pulmonary hypertension later in life.

A detailed histopathological study was made of the lungs of 36 cases of plexogenic pulmonary arteriopathy coming to combined heart‐lung transplantation. It revealed two dissimilar processes involved in the pathogenesis of this disease. One comprised histological appearances consistent with constriction of muscular pulmonary arteries, a condition that would be likely to be reversed by pulmanry vasodilators. The other was the proliferation of myofibroblasts in the intima and lumen of pulmonary arteries, a disorder of growth unlikely to be influenced by this type of therapy. In previous ultrastructural studies we have shown that the source of these cells of muscular pedigree is muscle cells from the inner half of the media which migrate into the intima through gaps in the inner elastic lamina. In the present study we found a similar proliferation of myofibroblasts in the intima, not only of pulmonary arteries, but also of pulmonary veins, in plexogenic pulmonary arteriopathy. Arterial thrombi found were considered to be a complication rather than a cause of plexogenic pulmonary arteriopathy. Siderophages, cholesterol granulomas and focal fibrosis in the lung were considered to be a consequence of intrapulmonary haemorrhage early in the course of the disease. It is concluded that, while plexogenic pulmonary arteriopathy has an important vasoconstrictive element, it is also based on a disorder of growth of cells of muscular pedigree. This view has clear implications for the therapy of primary plexogenic pulmonary arteriopathy.

A study was made of the qualitative histological features of the small pulmonary arterial vessels of 25 adult citizens of La Paz, Bolivia (altitude 3600 m) coming to necropsy. Abnormalities found included muscularization of pulmonary arterioles, the development of longitudinal muscle in the intima of pulmonary arteries and arterioles, and the formation of muscular tubes lining the longitudinal muscle which extended through arterioles into the precapillaries of the lung. Arteriolar muscularization was found in three of the 13 Aymaras and in two of the 12 Mestizos studied. Intimal longitudinal muscle was present in four Aymaras and five Mestizos. Muscular tubes were found in only one case, a young Aymara. The features were very similar to those found in chronic obstructive airways disease. The appearances are consistent with a growth of new vascular smooth muscle in response to alveolar hypoxia as opposed to hypoxic vasoconstriction.

A histological study was made of the carotid bodies and glomus pulmonale in 50 consecutive subjects over the age of 50 years who came to necropsy to determine if chronic glomitis is confined to the carotid bodies or whether it also occurs in other glomera. Lymphoid aggregates and plasma cell activity were found in the glomus pulmonale just as they were in the carotid bodies. Chronic pulmonary glomitis sometimes occurred in association with chronic carotid glomitis and sometimes independently of this. The mean age of the affected subjects was 76 years in isolated pulmonary glomitis and 79 years in chronic carotid glomitis. Chronic carotid glomitis affected seven (14%) subjects and predominated in women (six to one). In the seven cases of isolated pulmonary glomitis women predominated five to two. Chronic glomitis seems to be a disease process which may affect at least two members of the non-chromaffin paraganglionic system, but it is not clear why focal chronic inflammation affects the glomus pulmonale of one person but not of another.

Human carotid bodies obtained at necropsy that showed prominence of either the sustentacular cell or the dark variant of chief cell or chronic carotid glomitis were studied by an immunogold labeling technique. The peptides methionine and leucine enkephalin had a similar distribution to that found in the normal human carotid body. They were localized prominently and predominantly in the dark and progenitor variants of chief (type I) cells. The sustentacular (type II) cells showed no immunoreactivity for the enkephalins. Cell counts on immunolabeled chief cells in cases of sustentacular cell hyperplasia and chronic carotid glomitis were found to be at the lower end of the normal range, whereas those in dark cell prominence occurred nearer the upper limit.

A histological study was made of the carotid bodies obtained at necropsy in 40 fetuses, neonates, infants and young children, ranging in age from 23 weeks of gestation to 11 years of age. Prominence of the dark variant of chief cells was found in diseases such as bronchiolitis which are associated with sustained hypoxaemia. Such cells have copious cytoplasm known to be rich in peptides such as enkephalins. The same histological features were found in two cases clinically diagnosed as sudden infant death syndrome but in which there was associated bronchiolitis and tracheobronchitis respectively, thought to have given rise to hypoxaemia. In a case of sudden infant death syndrome without infection there was overgrowth of sustentacular cells with predominant progenitor cells in the absence of dark cells. We associate this appearance with inability of the carotid bodies to respond adequately to changes in arterial oxygen tension.

A study of the numbers of pulmonary endocrine cells per cm2 of section of lung obtained at combined heart-lung transplantation in 25 cases of plexogenic pulmonary arteriopathy demonstrated that the peptide which may become unduly prominent in pulmonary arterial disease is bombesin. The type of vascular disease in which bombesin becomes prominent is plexogenic pulmonary arteriopathy, be this primary or secondary to congenital heart disease. The increased prominence of bombesin appears to be related to the stage reached in the arteriopathy. Increased numbers of pulmonary endocrine cells are found in association with classic cellular plexiform lesions with narrow vascular channels. Their numbers are within normal limits when the plexiform lesions are mature with wide vascular channels and narrow intervening septa. The pulmonary endocrine cells are most prominent in the pre-plexiform stage when smooth muscle cells in the inner half of the media of the pulmonary artery show increased electron density, and migrate through gaps in the inner elastic lamina to reach the intima. Here they are transformed into myofibroblasts and proliferate. The migration of muscle cells may be related in some way to long-acting trophic factors released from the pulmonary endocrine cells into the surrounding tissues from which they reach the blood and hence the pulmonary arteries.