Rapid intravenous saline infusion, a model meant to replicate the initial changes leading to pulmonary interstitial edema, increases pulmonary arterial pressure in humans. We hypothesized that this would alter lung perfusion distribution. Six healthy subjects (29±6 years) underwent magnetic resonance imaging to quantify perfusion using arterial spin labeling. Regional proton density was measured using a fast-gradient echo sequence, allowing blood delivered to the slice to be normalized for density and quantified in mL/min/g. Contributions from flow in large conduit vessels were minimized using a flow cut-off value (blood delivered > 35% maximum in mL/min/cm3) in order to obtain an estimate of blood delivered to the capillary bed (perfusion). Images were acquired supine at baseline, after infusion of 20 mL/kg saline, and after a short upright recovery period for a single sagittal slice in the right lung during breath-holds at functional residual capacity. Thoracic fluid content measured by impedance cardiography was elevated post-infusion by up to 13% (p<0.0001). Forced expiratory volume in one second was reduced by 5.1% post-20 mL/kg (p=0.007). Infusion increased perfusion in nondependent lung by up to 16% (6.4±1.6mL/min/g baseline, 7.3±1.8 post, 7.4±1.7 recovery, p=0.03). Including conduit vessels, blood delivered in dependent lung was unchanged post-infusion; however, was increased at recovery (9.4±2.7 mL/min/g baseline, 9.7±2.0 post, 11.3±2.2 recovery, p=0.01). After accounting for changes in conduit vessels, there were no significant changes in perfusion in dependent lung following infusion (1.5±0.5 mL/min/g baseline, 1.5±0.4 post, 1.6±0.5, p=0.72). There were no significant changes in lung density. These data suggest that saline infusion increased perfusion to nondependent lung, consistent with an increase in intravascular pressures. Dependent lung may have been “protected” from increases in perfusion following infusion due to gravitational compression of the pulmonary vasculature.
arterial spin labeling; magnetic resonance imaging; pulmonary interstitial edema
Rats reared in hyperoxia have smaller carotid bodies as adults. To study the time course and mechanisms underlying these changes, rats were reared in 60% O2 from birth and their carotid bodies were harvested at various postnatal ages (P0-P7, P14). The carotid bodies of hyperoxia-reared rats were smaller than those of age-matched controls beginning at P4. In contrast, 7 days of 60% O2 had no effect on carotid body size in rats exposed to hyperoxia as adults. Bromodeoxyuridine (BrdU) and TdT-mediated dUTP nick end labeling (TUNEL) were used to assess cell proliferation and DNA fragmentation at P2, P4, and P6. Hyperoxia reduced the proportion of glomus cells undergoing cell division at P4; although a similar trend was evident at P2, hyperoxia no longer affected cell proliferation by P6. The proportion of TUNEL-positive glomus cells was modestly increased by hyperoxia. We did not detect changes in mRNA expression for proapoptotic (Bax) or antiapoptotic (Bcl-XL) genes or transcription factors that regulate cell cycle checkpoints (p53 or p21), although mRNA levels for cyclin B1 and cyclin B2 were reduced. Collectively, these data indicate that hyperoxia primarily attenuates postnatal growth of the carotid body by inhibiting glomus cell proliferation during the first few days of exposure.
glomus cell; cell proliferation; developmental plasticity; control of breathing; gene expression
Most behaviors have numerous components based on reflexes, but the neural circuits driving most reflexes rarely are documented. The nasotrigeminal reflex induced by stimulating the nasal mucosa causes an apnea, a bradycardia, and variable changes in mean arterial blood pressure (MABP). In this study we tested the nasotrigeminal reflex after transecting the brainstem at the pontomedullary junction. The nasal mucosae of anesthetized rats were stimulated with ammonia vapors and their brainstems then were transected. Complete transections alone induced an increase in resting heart rate (HR; p < 0.001) and MABP (p < 0.001), but no significant change in ventilation. However, the responses to nasal stimulation after transection were similar to those seen prior to transection. HR still dropped significantly (p < 0.001), duration of apnea remained the same, as did changes in MABP. Results from rats whose transection were incomplete are discussed. These data implicate that the neuronal circuitry driving the nasotrigeminal reflex, and indirectly the diving response, is intrinsic to the medulla and spinal cord.
diving response; cardiovascular; respiration; heart rate; medulla; SIDS
We investigated whether spinalized animals can produce inspiratory rhythm. We recorded spinal inspiratory phrenic (PNA) and cranial inspiratory hypoglossal (HNA) nerve activity in the perfused brainstem preparation of rat. Complete transverse transections were performed at 1.5 (pyramidal decussation) or 2 mm (first cervical spinal segment) caudal to obex. Excitatory drive was enhanced by either extracellular potassium, hypercapnia or by stimulating arterial chemoreceptors. Caudal transections immediately eliminated descending network drive for PNA, while the cranial inspiratory HNA remained unaffected. After transection, PNA bursting remained sporadic even during enhanced excitatory drive. This implies, cervical spinal circuits lack intrinsic rhythmogenic capacity. Rostral transections also abolished PNA immediately. However, HNA also progressively lost its amplitude and rhythm. Chemoreceptor activation only triggered tonic, non-rhythmic HNA. Thus the integrity of ponto-medullary circuitry was maintained. Our results suggest that an area overlapping the caudal nucleus retroambiguus provides critical ascending input to the ponto-medullary respiratory network for inspiratory rhythm generation.
nucleus retroambiguus; respiratory rhythm generation; spinal cord
Isolated in vitro brainstem-spinal cord preparations are used extensively in respiratory neurobiology because the respiratory network in the pons and medulla is intact, monosynaptic descending inputs to spinal motoneurons can be activated, brainstem and spinal cord tissue can be bathed with different solutions, and the responses of cervical, thoracic, and lumbar spinal motoneurons to experimental perturbations can be compared. The caveats and limitations of in vitro brainstem-spinal cord preparations are well-documented. However, isolated brainstem-spinal cords are still valuable experimental preparations that can be used to study neuronal connectivity within the brainstem, development of motor networks with lethal genetic mutations, deleterious effects of pathological drugs and conditions, respiratory spinal motor plasticity, and interactions with other motor behaviors. Our goal is to show how isolated brainstem-spinal cord preparations still have a lot to offer scientifically and experimentally to address questions within and outside the field of respiratory neurobiology.
Hypothyroidism can depress breathing and alter dopamine D2 receptor expression and function. We hypothesized that relative to euthyroid hamsters (EH), hypothyroid hamsters (HH) contain increased D2 receptors in brain regions associated with breathing and carotid bodies (CB), and that stimulation of D2 receptors would decease ventilation more in the HH compared to the EH. Hamsters were treated with vehicle, carmoxirile (peripherally acting D2 receptor agonist), or bromocriptine (central and peripherally acting D2 receptor agonist) and breathing was evaluated during exposure to air, hypoxia, and then air. HH exhibited increased D2 receptor protein levels in the striatum and CB’s, but decreased levels in the paraventricular hypothalamic nucleus. Relative to vehicle, carmoxirole and bromocriptine stimulated ventilation in the HH during and following exposure to hypoxia. Only bromocriptine depressed ventilation in the EH during and after exposure to hypoxia. Thus,, hypothyroidism impacts the expression of D2 receptors in the carotid body, PVN and striatum, and D2 stimulation affects ventilation remarkably differently than in EH.
Hypothyroidism; Dopamine D2 receptors; Hypoxia; Ventilation
Microglia and astrocytes play complex roles following spinal cord injury (SCI), contributing to inflammatory processes that both exacerbate injury and promote functional recovery by supporting neuro-protection and neuroplasticity. The crossed phrenic phenomenon (CPP) is an example of respiratory plasticity in which C2 cervical hemisection (C2HS) strengthens crossed-spinal synaptic pathways to phrenic motor neurons ipsilateral to injury. We hypothesized that microglia and astrocytes are activated in the phrenic motor nucleus caudal and ipsilateral to C2HS, suggesting their potential for involvement in the CPP. To test this hypothesis, an incomplete cervical spinal hemisection (C2 lateral injury; C2LI) was performed, and rats were allowed to recover for 1, 3, 14 or 28 days before collecting perfused spinal tissues. Microglia (via OX42) and astrocytes (via GFAP) were visualized with immunofluorescence microscopy in the C4-C5 ventral horn, the region encompassing most of the phrenic motor nucleus. OX42-occupied fractional area ipsilateral to injury increased with C2LI (vs. sham) at 1 (12.5 +/- 1.8%, p<0.001), 3 (29.0 +/- 1.9%, p<0.001), 14 (26.1 +/- 3.1%, p<0.001) and 28 (19.2 +/- 2.0%, p<0.001) days post-C2LI. GFAP-occupied fractional area also increased with C2LI at 3 (24.4 +/- 3.2%, p<0.001) and 14 (16.8 +/- 8.3%, p=0.012) days, but not at 1 (6.2 +/- 3.9%, p=0.262) or 28 (10.6 +/- 3.9%, p=0.059) days post-C2LI. Thus, microglia and astrocytes are activated in the phrenic motor nucleus caudal to C2LI, suggesting that they play a role in functional deficits and/or recovery following spinal injury.
astrocyte; microglia; phrenic; inflammation; crossed-phrenic
The diaphragm muscle (DIAm) is a highly active muscle of mixed fiber type composition. We hypothesized that consistent with greater activation history and proportion of fatigue-resistant fibers, neuromuscular transmission failure is lower in the mouse compared to the rat DIAm, and that neuromuscular junction (NMJ) morphology will match their different functional demands. Minute ventilation and duty cycle were higher in the mouse than in the rat. The proportion of fatigue-resistant fibers was similar in the rat and mouse; however the contribution of fatigue-resistant fibers to total DIAm mass was higher in the mouse. Neuromuscular transmission failure was less in mice than in rats. Motor end-plate area differed across fibers in rat but not in mouse DIAm, where NMJs displayed greater complexity overall. Thus, differences across species in activation history and susceptibility to neuromuscular transmission failure are reflected in the relative contribution of fatigue resistant muscle fibers to total DIAm mass, but not in type-dependent morphological differences at the NMJ.
Motor unit; plethysmography; morphometry; respiratory muscles; fiber type
There is evidence for a “sensitive period” in respiratory development in rats around postnatal age (P) 12-13d. Little is known about sex differences during that time. The purpose of this study was to assess the effect of sex on breathing development, specifically around the “sensitive period”. We used whole-body plethysmography to study breathing in normoxic, hypoxic and hypercapnic gases in non-anesthetized male and female neonatal rats from P10-P15, juvenile (P30) and young adult (P90) rats. Compared to other neonatal ages, P12-13 male rats had significantly lower ventilation during normoxia, hypoxia, and hypercapnia. Compared to age-matched females, P12-13 male rats had lower ventilation in normoxia and hypoxia and a lower O2 saturation during hypoxia. Circulating estradiol was greater in P12-13 male vs. female rats. Estradiol and ventilatory responses to hypoxia and hypercapnia were negatively correlated in neonatal male, but not female, rats. Our results suggest that P10-P15 includes a critical developmental period in male but not female rats.
Proteolipid protein (Plp) gene mutation in rodents causes severe CNS dysmyelination, early death, and lethal hypoxic ventilatory depression (Miller et al. 2004). To determine if Plp mutation alters neuronal function critical for control of breathing, the nucleus tractus solitarii (nTS) of four rodent strains were studied: myelin deficient rats (MD), myelin synthesis deficient (Plpmsd), and Plpnull mice, as well as shiverer (Mbpshi) mice, a myelin basic protein mutant. Current-voltage relationships were analyzed using whole-cell patch-clamp in 300μm brainstem slices. Voltage steps were applied, and inward and outward currents quantified. MD, Plpmsd, and Plpnull, but not Mbpshi neurons exhibited reduced outward current in nTS at P21. Apamin blockade of SK calcium-dependent currents and iberiotoxin blockade of BK calcium-dependent currents in the P21 MD rat demonstrated reduced outward current due to dysfunction of these channels. These results provide evidence that Plp mutation specifically alters neuronal excitability through calcium-dependent potassium channels in nTS.
myelin proteolipid protein; BK channel; SK channel; Plpnull mouse; Plpmsd mouse; Mbpshi mouse; Pelizaeus-Merzbacher disease
The aim of this study was to determine the relationship between airway blood flow (Q̇aw), airway conductance (Gf-aw) and pulmonary function in patients with stable HF. 12 controls (CTRL: age=63±9yr, FVC=98±15%pred, LVEF=61±6%) (all data presented as mean±SD), 16 patients with mild HF (HF-A, NYHA I–II: age=64±9yr, FVC=90±17%pred, LVEF=28±6%), and 14 patients with moderate/severe HF (HF-B, NYHA III–IV: age=65±6yr, FVC=84±12%pred, LVEF=26±6%) were studied. Q̇aw was assessed using soluble gas measurements; perfusion pressure across airway bed (ΔPaw) was estimated from systemic and pulmonary pressure measurements; Gf-aw was calculated as Q̇aw/ΔPaw; PF was assessed by spirometry. While Q̇aw was not significantly different between CTRL (61.3±17.9 μL·min−1·ml−1), HF-A (70.1±26.9 μL·min−1·ml−1) and HF-B (56.2±14.9 μL·min−1·ml−1) groups, Gf-aw, was elevated in HF-A (1.1±0.4 μL·min−1·ml−1·mmHg−1, p<0.03) and tended to be elevated in HF-B (1.2±0.6 μL·min−1·ml−1·mmHg−1, p=0.07) when compared to CTRL (0.8±0.3 μL·min−1·ml−1·mmHg−1). Significant positive correlations were found between Gf-aw and RV/TLC for HF-A (r=0.63, p<0.02) and HF-B (r=0.58, p<0.05). These results support the hypothesis that increased bronchial conductance and bronchial congestion may be related to greater small airway obstruction and as such may play a role in the PF abnormalities and symptoms of congestion commonly observed in HF patients.
Congestion; Left Ventricular Dysfunction; Bronchial Blood Flow
Synaptic inputs to cardiac vagal neurons (CVNs) regulate parasympathetic activity to the heart. Previous work has shown insults such as hypoxia and hypercapnia (H/H) alter CVN activity by activating post-synaptic serotonergic, purinergic, and glutamatergic receptors in CVNs. This study examines the role of serotonergic 5HT1A receptors in modulating these excitatory neurotransmissions to CVNs during control conditions, H/H and recovery from H/H. Excitatory post-synaptic currents (EPSCs) were recorded from identified CVNs in-vitro before, during and post H/H. The 5HT1A receptor antagonist WAY 100635 had no effect on EPSCS in CVNs before, and during H/H. However during recovery from H/H inspiratory-related excitatory serotonergic and purinergic pathways were recruited to excite CVNs. However when these serotonergic and purinergic pathways are blocked, the 5HT1A receptor antagonist WAY 100635 restores an excitatory glutamatergic neurotransmission to CVNs. This study indicates endogenous activation of serotonergic 5HT1A receptors diminishes glutamatergic neurotransmission to CVNs following H/H, likely via a presynaptic site of action.
parasympathetic; serotonin; hypoxia; hypercapnia; ambiguus; cardiac; heart rate; apnea; SIDS
TIMAP is a regulatory subunit of protein phosphatase 1, whose role remains largely unknown. Our recent data suggested that TIMAP is involved in the regulation of barrier function in cultured pulmonary endothelial monolayers (Csortos et al., Am J Physiol Lung Cell Mol Physiol 295: L440-450, 2008). Here we showed that TIMAP depletion exacerbates lipopolysaccharide (LPS)-induced vascular leakage in murine lung, suggesting that TIMAP has a barrier-protective role in vivo. Real-Time RT PCR analysis revealed that treatment with LPS significantly suppressed Timap mRNA level. This suppression was not achieved via the down-regulation of Timap promoter activity, suggesting that LPS decreased Timap mRNA stability. Pretreatment with protein kinase A (PKA) inhibitor H-89 reduced TIMAP mRNA level, whereas pretreatment with PKA activator, bnz-cAMP, increased this level and attenuated LPS-induced decrease in TIMAP mRNA. Altogether, these data confirmed the barrier-protective role of TIMAP and suggested that barrier-disruptive and barrier-protective agents may employ modulation of TIMAP expression as a mechanism affecting barrier permeability.
TIMAP; PPP1R16B; LPS; PKA; barrier dysfunction
Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na+ Channels (ENaC) regulate Na+ and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n= 17vs.13, age=25±7vs.30±10yrs., BMI= 23±4vs.25±4kg/m2, V̇O2peak= 95±30vs.100±31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DLCO), the diffusing capacity of the lungs for nitric oxide (DLNO), alveolar volume (VA), and alveolar-capillary membrane conductance (DM) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DLCO and DLNO, and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DLCO=51±12vs.36±17%, DLNO=51±24vs.32±25%, SVR=−67±3vs.−50±8%, p<0.05). The AA ENaC group also tended to have a greater percent increase in DLCO/VA from rest to peak exercise, although this did not reach statistical significance (49±26vs.33±26%, p=0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na+ and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.
DLCO; DLNO; polymorphism; lung fluid balance; epithelial sodium channel
Epithelial Na+ Channels (ENaC) are located on alveolar cells and are important in β2-adrenergic receptor-mediated lung fluid clearance through the removal of Na+ from the alveolar airspace. Previous work has demonstrated that genetic variation of the alpha subunit of ENaC at amino acid 663 is important in channel function: cells with the genotype resulting in alanine at amino acid 663 (A663) demonstrate attenuated function when compared to genotypes with at least one allele encoding threonine (T663, AT/TT). We sought to determine the influence of genetic variation at position 663 of ENaC on exhaled Na+ in healthy humans. Exhaled Na+ was measured in 18 AA and 13 AT/TT subjects (age=27±8 vs. 30±10yrs., ht.=174±12 vs. 171±10cm., wt=68±12 vs. 73±14kg., BMI=22±3 vs. 25±4kg/m2, mean±SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90 minutes following the administration of a nebulized β2-agonist (albuterol sulfate, 2.5mg diluted in 3ml normal saline). The AA group had a higher baseline level of exhaled Na+ and a greater response to β2-agonist stimulation (baseline= 3.1±1.8 vs. 2.3±1.5mmol/l; 30min-post= 2.1±0.7 vs. 2.2±0.8mmol/l; 60min-post= 2.0±0.5 vs. 2.3±1.0mmol/l; 90min-post= 1.8±0.8 vs. 2.6±1.5mmol/l, mean±SD, for AA and AT/TT, respectively, p<0.05). The results are consistent with the notion that genetic variation of ENaC influences β2-adrenergic receptor stimulated Na+ clearance in the lungs, as there was a significant reduction in exhaled Na+ over time in the AA group.
Breath Condensate; Airway Surface Fluid; Beta-agonist; SCNN1A; ADRB2; Gene
Upper airway muscles play an important role in regulating airway lumen and in increasing the ability of the pharynx to remain patent in the face of subatmospheric intraluminal pressures produced during inspiration. Due to the considerable technical challenges associated with recording from muscles of the upper airway, much of the experimental work conducted in human subjects has centered on recording respiratory-related activities of the extrinsic tongue protudor muscle, the genioglossus (GG). The GG is one of eight muscles that invest the human tongue (Abd-El-Malek, 1939). All eight muscles are innervated by the hypoglossal nerve (cranial nerve XII) the cell bodies of which are located in the hypoglossal motor nucleus (HMN) of the caudal medulla. Much of the earlier work on the respiratory-related activity of XII motoneurons was based on recordings obtained from single motor axons dissected from the whole XII nerve or from whole muscle GG EMG recordings. Detailed information regarding respiratory-related GG motor unit activities was lacking until as recently as 2006. This paper examines key findings that have emerged from the last decade of work conducted in human subjects. Wherever appropriate, these results are compared with results obtained from in vitro and in vivo studies conducted in non-human mammals. The review is written with the objective of facilitating some discussion and some new thoughts regarding future research directions. The material is framed around four topics: a) Motor unit type, b) Rate coding and recruitment, c) Motor unit activity patterns, and d) A compartment based view of pharyngeal airway control.
Phrenic motoneurons (PMNs) provide a synaptic relay between bulbospinal respiratory pathways and the diaphragm muscle. PMNs also receive propriospinal inputs, although the functional role of these interneuronal projections has not been established. Here we review the literature regarding PMN discharge patterns during breathing and the potential mechanisms that underlie PMN recruitment. Anatomical and neurophysiological studies indicate that PMNs form a heterogeneous pool, with respiratory-related PMN discharge and recruitment patterns likely determined by a balance between intrinsic MN properties and extrinsic synaptic inputs. We also review the limited literature regarding PMN bursting during respiratory plasticity. Differential recruitment or rate modulation of PMN subtypes may underlie phrenic motor plasticity following neural injury and/or respiratory stimulation; however this possibility remains relatively unexplored.
phrenic; diaphragm; motoneuron; respiratory
Respiratory motoneurons provide the exclusive drive to respiratory muscles and therefore are a key relay between brainstem neural circuits that generate respiratory rhythm and respiratory muscles that control moment of gases into and out of the airways and lungs. This review is focused on postnatal development of fast ionotropic synaptic transmission to respiratory motoneurons, with a focus on hypoglossal motoneurons (HMs). Glutamatergic synaptic transmission to HMs involves activation of both non-NMDA and NMDA receptors and during the postnatal period co-activation of these receptors located at the same synapse may occur. Further, the relative role of each receptor type in inspiratory-phase motoneuron depolarization is dependent on the type of preparation used (in vitro versus in vivo; neonatal versus adult). Respiratory motoneurons receive both glycinergic and GABAergic inhibitory synaptic inputs. During inspiration phrenic and HMs receive concurrent excitatory and inhibitory synaptic inputs. During postnatal development in HMs GABAergic and glycinergic synaptic inputs have slow kinetics and are depolarizing and with postnatal development they become faster and hyperpolarizing. Additionally shunting inhibition may play an important role in synaptic processing by respiratory motoneurons.
Motoneuron; Hypoglossal; Synaptic; Development; Inhibition; Excitation
Because tongue position and stiffness help insure that the pharyngeal airspace is sufficiently open during breathing, the respiration-related behavior of the tongue muscles has been studied in detail, particularly during the last two decades. Although eight different muscles act upon the mammal tongue, we know very little about the respiration-related control of the majority of these, and almost nothing about how they work together as a complex electro-mechanical system. Other significant gaps include how hypoglossal motoneuron axons find their appropriate muscle target during development, whether the biophysical properties of hypoglossal motoneurons driving different muscles are the same, and how afferent information from cardiorespiratory reflex systems is transmitted from major brainstem integrating centers to the hypoglossal motoneuron pool. This brief review outlines some of these issues, with the hope that this will spur research in the field, ultimately leading to an improved understanding of the respiration-related control of the mammalian tongue musculature.
control of breathing; hypoglossal motoneurons; interneurons; tongue muscles
Intermittent hypoxia-induced long-term facilitation (LTF) is variably expressed in the motor output of several inspiratory nerves, such as the phrenic and hypoglossal. Compared to phrenic LTF (pLTF), less is known about hypoglossal LTF (hLTF), although it is often assumed that cellular mechanisms are the same. While fundamental mechanisms appear to be similar, potentially important differences exist in the modulation of pLTF and hLTF. The primary objectives of this paper are to: 1) review similarities and differences in pLTF and hLTF, pointing out knowledge gaps, and 2) present new data suggesting that reduced respiratory neural activity elicits differential plasticity in phrenic and hypoglossal output (inactivity-induced phrenic and hypoglossal motor facilitation, iPMF and iHMF), suggesting that these motor pool specific differences are not unique to LTF. Differences in fundamental mechanisms or modulation of plasticity among motor pools may confer the capacity to mount a complex ventilatory response to specific challenges, particularly in motor pools with different “jobs” in the control of breathing.
long-term facilitation; inactivity-induced phrenic motor facilitation; hypocapnia; inactivity; phrenic motor facilitation; control of breathing; plasticity; reduced respiratory neural activity; intermittent hypoxia; LTF; hypoglossal; phrenic; iPMF; iHMF
Phrenic motoneurons are located in the cervical spinal cord and innervate the diaphragm muscle, the main inspiratory muscle in mammals. Similar to other skeletal muscles, phrenic motoneurons and diaphragm muscle fibers form motor units which are the final element of neuromotor control. In addition to their role in sustaining ventilation, phrenic motor units are active in other non-ventilatory behaviors important for airway clearance such as coughing or sneezing. Diaphragm muscle fibers comprise all fiber types and are commonly classified based on expression of contractile proteins including myosin heavy chain isoforms. Although there are differences in contractile and fatigue properties across motor units, there is a matching of properties for the motor neuron and muscle fibers within a motor unit. Motor units are generally recruited in order such that fatigue-resistant motor units are recruited earlier and more often than more fatigable motor units. Thus, in sustaining ventilation, fatigue-resistant motor units are likely required. Based on a series of studies in cats, hamsters and rats, an orderly model of motor unit recruitment was proposed that takes into consideration the maximum forces generated by single type-identified diaphragm muscle fibers as well as the proportion of the different motor unit types. Using this model, eupnea can be accomplished by activation of only slow-twitch diaphragm motor units and only a subset of fast-twitch, fatigue-resistant units. Activation of fast-twitch fatigable motor units only becomes necessary when accomplishing tasks that require greater force generation by the diaphragm muscle, e.g., sneezing and coughing.
Passive limb movement (PLM) in humans induces a phasic hyperpnea, but the underlying physiological mechanisms remain unclear. We asked whether PLM in anesthetized rats would produce a similar phasic hyperpnea associated with an augmented ventilatory (V̇E) response to CO2 that is dependent on sciatic afferents. The animals underwent 5 min threshold PLM, 3 min hypercapnia (5% CO2), and their combination (CO2 exposure at the end of 2nd min of 5-min PLM) before and after bilateral transection of the sciatic nerves. We found that a threshold PLM evoked a phasic hyperpnea, similar to that denoted in humans, and an augmented (V̇E) response to CO2. Both responses were greatly diminished by sciatic nerve transection. Moreover, similar responses were also evoked by electrically stimulating the central end of the transected sciatic nerve. Our findings suggest an ability of the sciatic afferents to augment the (V̇E) response to CO2 that likely contributes to the PLM-induced hyperpnea.
passive exercise; chemosensitivity; hypoxia; blood pressure; heart rate
Many lung and central nervous system disorders require robust and appropriate physiological responses to assure adequate breathing. Factors undermining the efficacy of ventilatory control will diminish the ability to compensate for pathology, threatening life itself. Although most of these same disorders are associated with systemic and/or neuroinflammation, and inflammation affects neural function, we are only beginning to understand interactions between inflammation and any aspect of ventilatory control (e.g. sensory receptors, rhythm generation, chemoreflexes, plasticity). Here we review available evidence, and present limited new data suggesting that systemic (or neural) inflammation impairs two key elements of ventilatory control: chemoreflexes and respiratory motor (vs. sensory) plasticity. Achieving an understanding of mechanisms whereby inflammation undermines ventilatory control is fundamental since inflammation may diminish the capacity for natural, compensatory responses during pathological states, and the ability to harness respiratory plasticity as a therapeutic strategy in the treatment of devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.
long-term facilitation; intermittent hypoxia; LPS; plasticity; respiratory motor neuron
Perinatal sepsis and inflammation trigger lung and brain injury in preterm infants, and associated apnea of prematurity. We hypothesized that endotoxin exposure in the immature lung would upregulate proinflammatory cytokine mRNA expression in the medulla oblongata and be associated with impaired respiratory control. Lipopolysaccharide (LPS, 0.1 mg/kg) or saline was administered intratracheally to rat pups and medulla oblongatas were harvested for quantifying expression of mRNA for proinflammatory cytokines. LPS-exposure significantly increased medullary mRNA for IL-1β and IL-6, and vagotomy blunted this increase in IL-1β, but not IL-6. Whole-body flow plethysmography revealed that LPS-exposed pups had an attenuated ventilatory response to hypoxia both before and after carotid sinus nerve transection. Immunochemical expression of IL-1β within the nucleus of the solitary tract and area postrema was increased after LPS-exposure. In summary, intratracheal endotoxin-exposure in rat pups is associated with upregulation of proinflammatory cytokines in the medulla oblongata that is vagally-mediated for IL-1β and associated with an impaired hypoxic ventilatory response.
Alveolar hypoxia occurs as a result of a decrease in the environmental PO2, as in altitude, or in clinical conditions associated with a global or regional decrease in alveolar ventilation. Systemic effects, in most of which an inflammatory component has been identified, frequently accompany both acute and chronic forms of alveolar hypoxia. Experimentally, it has been shown that acute exposure to environmental hypoxia causes a widespread systemic inflammatory response in rats and mice.
Recent research has demonstrated that alveolar macrophages, in addition to their well known intrapulmonary functions, have systemic, extrapulmonary effects when activated, and indirect evidence suggest these cells may play a role in the systemic consequences of alveolar hypoxia.
This article reviews studies showing that the systemic inflammation of acute alveolar hypoxia observed in rats is not initiated by the low systemic tissue PO2, but rather by a chemokine, Monocyte Chemoattractant Protein-1 (MCP-1, or CCL2) released by alveolar macrophages stimulated by hypoxia and transported by the circulation. Circulating MCP-1, in turn, activates perivascular mast cells to initiate the microvascular inflammatory cascade.
The research reviewed here highlights the extrapulmonary effects of alveolar macrophages and provides a possible mechanism for some of the systemic effects of alveolar hypoxia.
Alveolar hypoxia; alveolar macrophages; systemic inflammation; mast cells; MCP-1/CCL2