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From carotid body oxygen sensing to chronic intermittent hipoxia effects on spontaneous tumorigenesis. The journey of Constancio’s group

Other TitlesUn nuevo papel para el cuerpo carotídeo en la patología. Simposio en memoria del Profesor Constancio González
AuthorsGallego-Martin, Teresa ; Rocher, Asunción ; Agapito, Teresa ; Gómez-Niño, A.; Rigual, Ricardo ; Yubero, Sara ; Gonzalez-Obeso, Elvira; Olea, Elena ; Docio, Inmaculada; Obeso, Ana
Carotid body
Oxygen sensing
Intermittent hypoxia
Issue Date2016
CitationXXXVIII Congreso SECF (2016)
AbstractThe carotid body (CB) is a singular organ which senses variations of the arterial blood PO2, PCO2 and [H+]. In the middle of 1980s, based on our experimental data, our laboratory proposed the membrane hypothesis of acute hypoxic chemoreception formulating that the chemoreceptor cells decrease in arterial PO2 is detected by an oxygen sensor, and the reduction in the opening probability of O2-sensitive K+ channels (Lopez-Barneo et al., 1988) depolarizes chemoreceptor cells. Activation of voltage dependent Na+ and Ca2+ channels increases intracellular free [Ca2+] promoting release of catecholamines and other neurotransmitters, which augment the activity of the carotid sinus nerve producing hyperventilation (Gonzalez et al., 1994). Second messengers, such as cAMP, EPAC, and hydrogen sulphide, are capable to modulate the flow of information in the chemoreception transduction cascade (Rocher et al., 2009; Gallego-Martin et al., 2015). Nowadays, oxygen sensor identity remains unknown. Physiological systemic effects of CB activation have long been studied. In recent years, CB involvement in several pathological processes turns into a field of high interest. Some of these pathological processes are respiratory diseases that involve hypoxic situations, such as chronic sustained hypoxia in chronic obstructive pulmonary disease and chronic intermittent hypoxia (CIH) in obstructive sleep apnea (OSA). As a consequence of CIH, repetitive CB activation produces sympathetic overstimulation and redox imbalance, with high levels of reactive oxygen species (Agapito et al., 2009). CB overexcitation in OSA patients could be related to the appearance of cardiovascular pathologies (endotelial dysfunctions, hypertension, cardio- and cerebrovascular accidents), hepatometabolic alterations (obesity, insulin resistance, non-alcoholic hepatic steatosis), and neuropsychiatric diseases (anxiety, depression, dementia). Recently, it has been proposed a relationship between CIH, the main constitutive element of OSA, and cancer. Limited studies have evidenced that CIH augments growth and metastasis rate of implanted tumors in mice (Almendros et al 2013). In OSA patients, although with some discrepancies, an association between OSA and cancer incidence/mortality has been reported (Nieto et al., 2012). Discrepancies could be due to the large number of OSA-linked co-morbidities. Trying to simplify this complex pathological human situation, CIH as a single variable has been used to evaluate its effects on spontaneous tumorigenesis. In an old outbreed murine model, two intensities of CIH were applied (12% O2, moderate, and 7.5% O2, severe) mimicking two stages of OSA patients pathological situation. We have observed that long term (3 months) severe CIH augments spontaneous lung tumor incidence. These tumors are lung typical carcinoids, a type of neuroendocrine tumor. These findings could help to interpret cancer incidence in OSA patients and, on the other hand, they alert about the necessity of further designed human studies to evaluate if OSA could augment only specific types of cancer incidence.
DescriptionResumen del trabajo presentado al XXXVIII Congreso de la Sociedad Española de Ciencias Fisiológicas (SECF), celebrado en Zaragoza del 13 al 16 de septiembre de 2016.
Appears in Collections:(IBGM) Comunicaciones congresos
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