The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article.

Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body.

Minimal morbidity occurs with resection of most carotid body tumors (CBT). With larger tumors significant injury to the cranial nerves has been reported. In order to assess the operative sequelae rate, 30 patients with CBT were reviewed. Sixteen patients either presented with bilateral carotid body tumors or had previously undergone a resection of the contralateral carotid body tumors, for a total carotid body tumor count of 46. Sixteen patients demonstrated a familial pattern while 14 were nonfamilial. Within the familial group, 14 of 16 presented with multiple paragangliomas as compared to 6 of 14 in the nonfamilial group. Tumor size ranged from 0.8 to 12 cm. Vascular replacement occurred in 2 of 20 patients with tumors 5.0 cm. Four patients lost cranial nerves with the resection: superior laryngeal nerve (SLN), 4; cranial nerve X, 1; cranial nerve XII, 1. Ten patients developed baroreceptor failure secondary to bilateral loss of carotid sinus function. First-bite pain occurred in 10 of 25 operative patients. Cranial nerve loss can be minimal with resection of carotid body tumors, however, baroreceptor failure and first-bite pain are postoperative sequelae that are often disregarded in the postoperative period

Carotid body tumors: A review of 30 patients with 46 tumors

PURPOSE: To study the morphology of the murine optic nerve (ON).

METHODS: Eyes of C57/Bl6 and BalbC mice were studied by light and electron microscopy. Microvascular castings of the ON region were prepared by transcardial injection of liquid plastic and studied with a scanning electron microscope. Immunohistochemistry was performed using antibodies against glial fibrillary acidic protein (GFAP), connexin 43, carbonic anhydrase II, and collagen types I and III.

RESULTS: The transition between nonmyelinated and myelinated portion of the ON started approximately 0.6 mm behind the globe. A lamina cribrosa was completely absent. Instead, ON axons passed through a scleral hole that was surrounded by a ring of type III and type I collagen fibers. Instead of connective tissue beams within the nerve, layers of elongated astrocytes traversed the ON. All astrocytes stained for GFAP, but not for carbonic anhydrase II. The arterial supply of the nonmyelinated ON derived from branches of the central retinal artery. None of the capillaries derived from choroidal vessels.

CONCLUSIONS: The mouse ON head differs from that of other species, because it lacks a lamina cribrosa and a choroidal vascular supply. Studies in glaucomatous mice might help to identify the importance of the lamina cribrosa and the choroidal vascular supply for optic nerve damage in glaucoma.

Morphology of the murine optic nerve.

The carotid body (CB) is a neural crest-derived organ whose major function is to sense changes in arterial oxygen tension to elicit hyperventilation in hypoxia. The CB is composed of clusters of neuron-like glomus, or type-I, cells enveloped by glia-like sustentacular, or type-II, cells. Responsiveness of CB to acute hypoxia relies on the inhibition of O2-sensitive K+ channels in glomus cells, which leads to cell depolarisation, Ca2+ entry and release of transmitters that activate afferent nerve fibres. Although this model of O2 sensing is generally accepted, the molecular mechanisms underlying K+ channel modulation by O2 tension are unknown. Among the putative hypoxia-sensing mechanisms there are: the production of oxygen radicals, either in mitochondria or reduced nicotinamide adenine dinucleotide phosphate oxidases; metabolic mitochondrial inhibition and decrease of intracellular ATP; disruption of the prolylhydroxylase/hypoxia inducible factor pathway; or decrease of carbon monoxide production by haemoxygenase-2. In chronic hypoxia, the CB grows with increasing glomus cell number. The current authors have identified, in the CB, neural stem cells, which can differentiate into glomus cells. Cell fate experiments suggest that the CB progenitors are the glia-like sustentacular cells. The CB appears to be involved in the pathophysiology of several prevalent human diseases.

SERIES “HYPOXIA: ERS LUNG SCIENCE CONFERENCE” 

Edited by N. Weissmann 

Number 5 in this Series

https://erj.ersjournals.com/content/erj/32/5/1386.full.pdf

Carotid body oxygen sensing

The carotid bodies from 150 consecutive cases coming to necropsy were examined to determine the degree of anatomical variation of the organ. Single, double and bilobed variants were found. The origin of the carotid body was variable, the angle of the carotid bifurcation being the most typical, but a minority were encountered on the internal or external carotid arteries, the common carotid artery and the ascending pharyngeal artery. Carotid bodies which were enlarged had no preferred site or origin, but some showed early or pronounced nodularity. Both carotid bodies from 100 of these cases were subjected to detailed qualitative and quantitative histological study. From these measurements we were able to define hyperplasia of the organ as a differential sustentacular cell count in excess of 47 per cent., a lobular diameter over 565 micrometers, and a combined carotid body weight over 30 mg. Carotid body hyperplasia occurred in cases of myocardial hypertrophy secondary to both hypoxaemia and systemic hypertension.

Anatomical variation and quantitative histology of the normal and enlarged carotid body.

The histopathology of hyperplasia of the carotid bodies was studied in 6 cases of hypoxaemia and right ventricular hypertrophy secondary to pan-acinar emphysema, and in five cases of systemic hypertension with left ventricular hypertrophy. The features of the hyperplasia were the same in the two groups. There was proliferation of sustentacular (type II) cells and compression of central cores of chief (type I) cells. It is speculated that the hyperplasia of sustentacular cells is associated in some way with the prevention of retention of sodium ions and water which characterises hypoxic cor pulmonale in "blue bloaters", systemic hypertension, and ascent to high altitude with the complications of acute mountain sickness, and pulmonary and cerebral oedema.

Hyperplasia of the carotid body.

The histopathology of the enlarged carotid bodies, in both qualitative and quantitative terms, is described in two cases. One was in a woman of 80 years with systemic hypertension and the other in a man of 72 years with pan-acinar emphysema complicated by chronic hypoxaemia. In both instances there was generalized hyperplasia of sustentacular cells, perhaps with involvement of Schwann cells and fibrocytes, with superimposed focal proliferation of dark or 'pyknotic' variants of chief cells. The functional significance of both froms of tissue response in the carotid bodies is speculated upon.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1711420109

Dark cell proliferation in carotid body hyperplasia.

A histological and electron microscopical study was carried out on the vasculature of the carotid bodies in seven subjects coming to necropsy. None of these had suffered from chronic hypoxaemia or systemic hypertension during life and none had hypertrophy of the right or left ventricle. The vasculature of the carotid bodies showed three distinct components. There was a proximal portion, comprising elastic interlobular arteries, which had a wall in which elastic tissue predominated and in which many nerve fibrils could be demonstrated. This is considered to be baroreceptor in nature. There was an intermediate portion comprising muscular intralobular arterioles which are believed to be capable of controlling the level of blood supply to the parenchyma of the carotid bodies. Finally there are glomic capillaries surrounded by elongated pericytes and sustentacular cells. One or other of these elongated cells is thought to be responsible for the carotid body hyperplasia which is associated with systemic hypertension and states of chronic hypoxaemia.

The vasculature of the carotid body

The brilliant intuitative interpretation of the histology of the carotid body by de Castro in 1926 subsequently confirmed by the work of physiologists like Heymans et al (1930) and Comroe and Schmidt (1938), demonstrated conclusively that the carotid body has a chemoreceptor function. However, although half a century has passed since this discovery, the carotid body has been largely ignored by pathologists. Their interest in the organ is largely confined to its tumour, the chemodectoma, which has such a characteristic histological picture as to make it suitable for such exercises as the Final Practical Examination of the Royal College of Pathologists. Otherwise morbid anatomists have largely ignored the organ and it is exceptional to see the carotid bodies examined at necropsy even in a case of cardio-pulmonary disease. Little or nothing is written in undergraduate texts of pathology concerning the reactions of the carotid body in generalised disease and hence the ignorance is transmitted to the next generation. This has led to a peculiar imbalance in our knowledge of the carotid bodies. The physiologists have continued to carry out elegant and sophisticated studies on carotid bodies in animals but our knowledge of the condition of these organs in a wide range of diseases is meagre.

Carotid Body Hyperplasia

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