Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Abstract

Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields.

The impact of inflammation on respiratory plasticity

“…For example, ventilatory acclimatization to hypoxia involves a time-dependent increase in the hypoxic ventilatory response (HVR) during CSH (Pamenter and Powell, 2016) that is blocked by systemic application of the NSAID ibuprofen in rats (Popa et al, 2011). Ibuprofen during CSH also blocks increases in IL-1β and IL-6 expression in the nucleus tractus solitarii (NTS) of rats (Popa et al, 2011).…”

“…Ibuprofen during CSH also blocks increases in IL-1β and IL-6 expression in the nucleus tractus solitarii (NTS) of rats (Popa et al, 2011). The NTS is an important site for VAH the site of the primary synapse from carotid body chemoreceptors and exhibiting plasticity in glutamatergic neurotransmission that is necessary for VAH (reviewed by Pamenter and Powell, 2016). Together, these data suggest that inflammatory signals in the NTS are important for plasticity in VAH.…”

The hypoxia tolerance of eight related African mole‐rat species rivals that of naked mole‐rats, despite divergent ventilatory and metabolic strategies in severe hypoxia

“…The response to hypoxia in mammals may consist of increases in ventilation (to match O 2 supply to metabolic demand; the hypoxia ventilatory response), decreases in metabolic rate (to match metabolic demand to O 2 supply; the hypoxic metabolic response) or a combination of the two . It has long been hypothesized that repeated exposure to relative hypoxia and hypercarbia compared with surface gas composition (ie normoxia and normocarbia) has shaped the homeostatic responses to these conditions in semi‐fossorial and fully fossorial mammals, and that their greater reliance on metabolic depression and lesser reliance on ventilatory increases compared with non‐fossorial mammals contributes to their greater tolerance to hypoxia.…”

“…1,10 The response to hypoxia in mammals may consist of increases in ventilation (to match O 2 supply to metabolic demand; the hypoxia ventilatory response), decreases in metabolic rate (to match metabolic demand to O 2 supply; the hypoxic metabolic response) or a combination of the two. [11][12][13][14] It has long been hypothesized that repeated exposure to relative hypoxia and hypercarbia compared with surface gas composition (ie normoxia and normocarbia) has shaped the homeostatic responses to these conditions in semi-fossorial and fully fossorial mammals, 1,3 and that their greater reliance on metabolic depression and lesser reliance on ventilatory increases compared with non-fossorial mammals contributes to their greater tolerance to hypoxia. This is borne out in experimental evidence where non-fossorial mammals, which tend to be less tolerant to hypoxia, typically exhibit increases in total ventilation and little change to metabolic rate, 15 whereas fossorial and semi-fossorial mammals, which are typically more tolerant of hypoxia compared with non-fossorial mammals, exhibit a reduced ventilatory response in conjunction with various degrees of metabolic suppression.…”

Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia

“…On the other hand, neuronal elements upstream from respiratory pre‐motor neurons diverge considerably in these chemoreflexes. For example, hypoxic sensory perception occurs predominantly in peripheral, carotid body chemoreceptors that project through the glossopharyngeal nerve to the nucleus of the solitary tract; there, they are processed en route to the ventral respiratory group . Conversely, hypercapnic chemoreflexes are dominated by CO 2 sensitive chemoreceptors distributed throughout the brainstem, including the retrotrapezoid nucleus, nucleus of the solitary tract, raphe nuclei, and locus coeruleus .…”