Journal of applied physiology最新文献

Nicotine withdrawal after chronic exposure causes dysregulation of neural circuits, producing a variety of adverse signs and symptoms that are largely mediated through changes to nicotinic acetylcholine receptors (nAChRs). nAChRs are expressed throughout neural circuits mediating the hypoxic ventilatory response (HVR), however whether nicotine withdrawal impacts this critical chemoreflex is unknown. We tested the hypothesis that nicotine withdrawal blunts the HVR in rats. We exposed 6-week-old male and female Sprague-Dawley rats to chronic nicotine through their drinking water (0.2 g/L nicotine in 1% saccharin). Prior to experiments, half of the nicotine exposed rats were switched to saccharin water alone to produce a nicotine withdrawal group. Rats in the control group drank saccharin water alone. We used plethysmography to test the early- and late- phase ventilatory response to a 5-minute episode of 10% oxygen in all rats, corresponding to 6, 24, and 48 hours of withdrawal in the withdrawal group. In both male and female rats, serum cotinine was significantly reduced by 6 hours of nicotine withdrawal. In males, the HVR was not different between treatment groups. However, in females, while the HVR was the same in control rats and rats who continued nicotine exposure, both the early- and late-phase HVR were significantly blunted in animals in nicotine withdrawal. Nicotine withdrawal, although uncomfortable, is not considered dangerous. However, these results indicate that a blunted HVR is a previously unidentified consequence of nicotine withdrawal, which may help to explain the link between nicotine withdrawal and worse clinical outcomes in hospitalized patients.

Mechanical ventilation (MV) plays a vital role in intensive care, ensuring sufficient gas exchange in acute respiratory distress syndrome (ARDS) patients. However, ventilator-induced lung injury (VILI) remains a frequent complication associated with MV, arising due to local lung tissue hyperinflation (HI) and cyclic alveolar recruitment/derecruitment (R/D). Determining optimal ventilator settings is a clinical challenge, since the full spectrum of local lung mechanics in a heterogenous lung cannot be assessed with overall mechanical measurements, nor with routine imaging modalities. Computational modelling offers a promising approach for personalizing mechanical ventilation settings, by predicting the local lung mechanical behavior. We propose an in silico model of the respiratory system of a mechanically ventilated ARDS patient, which integrates local patient-specific lung characteristics. These include both structural (airway tree and lung morphology) and functional (regional lung elastance and R/D dynamics) information, inferred from computed tomography (CT) data obtained at two different respiratory pressure instances. Our proof-of-principle simulations indicate that the model plausibly estimates the global respiratory pressure-volume curve, as well as regional lung biomechanical behavior, under positive pressure ventilation. Further, we show that this model can be used to simulate the effect of changes in ventilator settings such as positive end-expiratory pressure (PEEP), or to simulate an impaired lung with worsening biomechanics. This model thereby provides a mechanistic foundation to eventually support clinicians in delivering more precise, patient-specific therapies, by offering a supplementary tool for optimizing ventilator settings.

Dyspnea is the symptom that conveys the upsetting or distressing awareness of respiratory sensations. It is part of an ensemble of respiratory, neurovegetative, and behavioral manifestations resulting from the brain's reaction to abnormal respiratory-related afferents. This attests to a systemic phenomenon and suggests the existence of measurable biological changes. Different types of experimental respiratory challenges evoke different perceptual, physiological and psychological responses, suggesting distinct mechanisms and the possibility of varied systemic biological responses. We investigated this hypothesis in 34 healthy volunteers (17 women) exposed to inspiratory threshold loading (ITL) and carbon dioxide stimulation with restricted ventilation (CO2-rv), in a randomized cross-over design. Blood and saliva samples were collected at baseline (T0), at the end of a 5-minute dyspnea challenge (T1), and at 30 and 60 minutes post-challenge (T2 and T3). They were analyzed for neuromodulators and inflammatory biomarkers. Substance P levels rose at all time points during both challenges, but were significantly higher after CO2-rv than after ITL. β-endorphin levels rose similarly after both challenges, with a correlation to affective dyspnea ratings during ITL only (R=0.527, p=0.0023). Brain-derived neurotrophic factor (BDNF) decreased after both stimuli, with lower values following ITL. There were no significant changes in salivary alpha-amylase, FGF-2, TNF-α, IL-1β, IL-8, or IDO/TDO activity, and salivary cortisol decreased. These results provide a biological substrate for the differences between responses to respiratory challenges. They open new avenues toward biology-guided research into respiratory-related brain suffering.

There are several sex differences in cardiovascular morphology. Specifically, females have smaller cardiac chambers compared to males. Whether smaller left ventricular (LV) size contributes to higher filling pressures during dynamic exercise is unknown. We tested the hypothesis that smaller LV volumes and smaller stroke volume (SV) reserve in young females would be associated with greater LV filling pressures. Methods. Fourteen young males (n=7; 34±3yrs; 48.1±4.5 ml/kg/min) and females (n=7; 31±3yrs; V̇O_2peak 39.6±4.1 ml/kg/min) completed a maximal exercise test and an invasive exercise test with right heart catheterization. Hemodynamic response, including pulmonary capillary wedge pressure (PCWP), cardiac output and SV (direct Fick), were measured during upright rest and cycle exercise at a standard absolute heart rate of 100bpm, as well as 70 and 90% HR max. Results. Females had a greater PCWP during exercise (p=0.038), specifically when heart rate was matched at 100 bpm (males: 7±3, females: 10±2 mmHg, p=0.040) and at 90% HRmax (males: 8±3, females: 14±3 mmHg, p=0.006). Females also had a smaller SV reserve (46±19 %) than males (70±20 %, p=0.076). There was an inverse relationship between change in SV with exercise and PCWP (r²=0.22, p=0.003). The PCWP-cardiac output slope was significantly greater in females (0.9 ± 0.3 mmHg/L/min) than males (0.3 ± 0.2 mmHg/L/min, p=0.004). Conclusion. Females have higher PCWP for a given cardiac output and lower SV during exercise than males. These findings suggest smaller, absolute LV volumes are less distensible which may contribute to apparent sex differences in adaptations to chronic endurance training and performance.

Revealing biological mechanisms leading to respiratory muscle dysfunction is essential to improve clinical outcomes in patients with critical illness. The purpose was to identify biological mechanisms associated with respiratory muscle dysfunction in patients with critical illness during mechanical ventilation or sepsis. Six databases were electronically searched from inception to January 2025 examining studies with muscle biopsies. Screening, data collection, and risk-of-bias were conducted in duplicate by two independent assessors. Meta-analysis was performed to determine differences in muscle biological parameters of patients with critical illness requiring mechanical ventilation compared to controls. From 22,036 titles screened, eight studies (n=187 patients and n=161 controls) published between 2000-2024 met eligibility criteria. Muscle biopsies were taken between days 1-7 in the intensive care unit from diaphragm (n=110; 3 studies), rectus abdominis (n=68; 5 studies), external intercostal (n=10; 1 study), and latissimus dorsi (n=3; 1 study). Diaphragmatic fiber cross-sectional area was 30% smaller (mean difference [95% confidence interval] =-629 [-876, -382] μm²), with lower proportion of type II fibers (-1.94 [-3.40, -0.49] %) compared with controls. Diaphragmatic fiber force of patients was more than two standard deviations lower (Standardized mean difference=-2.49 [-3.84, -1.14]) and ubiquitinated protein levels were higher (2.09 [-0.14, 4.32]) than controls. Extramyocellular, mitochondrial, and gene expression parameters were assessed in some studies, but low sample size and high heterogeneity prevented meta-analyses. In conclusion, muscle biopsies from ventilated patients revealed atrophy, contractile weakness, and proteolysis markers. Standardized methodologies assessing respiratory muscles are needed to clarify biological mechanisms leading to muscle dysfunction and to guide respiratory muscle interventions.

Mechanical ventilation contributes to lung injury in acute respiratory distress syndrome, yet whether cumulative mechanical energy, the time-integrated delivery of ventilatory power, adequately reflects the risk of ventilator-induced lung injury (VILI) remains uncertain. Because lung tissue exhibits nonlinear stress-strain behaviour, the rate and amplitude of energy delivered may be as relevant as its magnitude. We tested whether different combinations of tidal volume (VT) and ventilation duration, matched for cumulative energy, produce distinct patterns of VILI following endotoxin-induced lung damage in male Wistar rats. Animals received intratracheal lipopolysaccharide and, after 24 h, were mechanically ventilated (PEEP=3 cmH₂O; inspired oxygen fraction=0.40) using one of three strategies: VT=6 mL/kg for 150 min (LVT-HMV), VT=9 mL/kg for 100 min (MVT-MMV), or VT=12 mL/kg for 75 min (HVT-LMV). Apparatus dead space was adjusted to maintain normocapnia. An LPS-exposed, non-ventilated group served as molecular and histological reference. Despite equivalent cumulative energy exposure, HVT-LMV resulted in higher plateau and driving pressures, greater alveolar overdistension, collapse, and pulmonary edema, and increased expression of interleukin-6 and vascular cell adhesion molecule-1. MVT-MMV produced intermediate structural injury with selective upregulation of mechanosensitive extracellular matrix markers, whereas LVT-HMV was associated with the least injury. Driving and plateau pressures correlated with indices of overdistension and extracellular matrix signaling but showed weaker associations with endothelial activation. These findings indicate that VILI depends not only on total energy delivery but also on its temporal distribution, and that cumulative energy alone is insufficient to predict lung injury risk.

Histamine released within skeletal muscle facilitates sustained postexercise vasodilation and contributes to the development of training adaptations. Quantifying the histamine response is challenging because histamine is rapidly broken down and metabolized. Thus, we explored the use of histamine's metabolites, 1-methylhistamine and 1-methylimidazole acetic acid, as biomarkers of the histamine response to exercise. We hypothesized that plasma concentrations and urinary production of these metabolites would increase following aerobic and resistance exercise. Twelve (1 female, 11 male) participants (VO_2peak: 51.9±6.9 mL·kg^-1·min^-1; back squat 1-repetition maximum, 1-RM: 1.59±0.26 kg/bodyweight) completed two separate exercise sessions: Aerobic (30 min of cycling at 70% VO_2peak) and resistance (6 sets of 10 repetitions of back squats at 10-RM). Femoral artery blood flow was measured, and blood samples were obtained before, immediately after, and throughout 2 h of postexercise recovery. Urine was collected 24 h before exercise, from the start of exercise until 2 h after exercise, and for 24 h after exercise. Plasma concentrations of 1-methylhistamine and 1-methylimidazole acetic acid increased following both exercise sessions (p<0.05). Likewise, urine production rates of 1-methylhistamine and 1-methylimidazole acetic acid increased following both exercise sessions (p<0.05). Further, receiver operating characteristic analysis for 1-methylimidazole acetic acid found strong evidence that urine production rates correctly discriminate between conditions (likelihood ratio 12, p<0.01; area under the curve 0.80, p<0.01). Thus, urine production rates of 1-methylhistamine and 1-methylimidazole acetic acid demonstrate utility as a biomarker of the histamine response to exercise.

Rationale: Inspiratory duty cycle (IDC), the fraction of inspiratory time relative to total breath duration, serves as an adaptive response to flow limited ventilation in obstructive sleep apnea (OSA). IDC compensation remains incompletely characterized in the context of OSA pathophysiology. We studied the relationship of IDC and flow-limited breathing in OSA during drug induced sleep endoscopy (DISE). Methods: Eighty-two adults with OSA underwent DISE with continuous positive airway pressure (CPAP) titration. Airflow (V_I), tidal volume (TV), and IDC were measured across varying levels of flow-limited breathing. Airway collapsibility was assessed by pharyngeal opening (P_open) and critical closing pressures (P_crit). IDC compensation was quantified as the slope of IDC versus normalized TV (%P_openTV), representing the degree of IDC increase to declining ventilation. Patients were classified as high versus low IDC compensators based on this slope metric and differences in P_open and P_crit were compared between groups. Results: As CPAP increased from flow-limited to non-flow-limited breathing, IDC decreased by 20% while TV and ventilation more than doubled. IDC compensation varied among subjects with stronger compensators exhibiting higher airway collapsibility (P_open = 10.2 vs. 8.2cmH₂O; p = 0.01, P_crit = 4.2 vs. 3.0cmH₂O; p = 0.03). Conclusions: IDC compensation reflects a physiological response that helps maintain ventilation under flow-limited conditions. Greater airway collapsibility was associated with stronger IDC compensation, reflecting the capacity of the respiratory system to tolerate increased mechanical load. DISE provides a unique experimental platform to quantify ventilatory timing responses, advancing our mechanistic understanding of respiratory compensation in OSA.

Advanced glycation end-products (AGEs) accumulate with age and may contribute to skeletal muscle decline, yet their distribution within muscle compartments is unknown. Resistance training (RT) and high-intensity interval training (HIIT) improve muscle function, but their effects on muscle AGEs remain unexplored. Polyphenols have antioxidant properties, which could limit AGE formation. This study investigated AGE accumulation in different muscle compartments and whether a 12-week RT + HIIT intervention, with or without polyphenol supplementation could modify AGE levels. Forty-one healthy middle-aged and older adults (55-70 years) were randomized to receive a polyphenol-rich berry extract or placebo for 30 days, followed by 12 weeks of supervised RT + HIIT. Vastus lateralis biopsies were collected before and after the intervention and analyzed for subtypes of AGEs using immunofluorescence. AGE immunoreactivity was quantified in type I and type II fibers and in the extracellular matrix (ECM). AGE immunoreactivity was higher in type I than type II fibers (p < 0.0001) and most pronounced in the ECM (p < 0.05 vs. both fiber types). AGE signals did not differ between sexes and were unrelated to age or plasma IL-6. Neither training nor polyphenol supplementation altered AGE content in fibers or ECM. These findings provide the first evidence of fiber-type-associated localization of AGE immunoreactivity in humans. The absence of change following 12 weeks of RT and HIIT, with or without polyphenol, suggests that AGE turnover in skeletal muscle is limited in short-term interventions, highlighting the need for longer strategies to reduce AGE accumulation.

Prolonged low-frequency force depression (PLFFD) is the disproportionate loss of force in response to low-frequencies (e.g., <20Hz) of activation compared to high-frequencies (e.g., >50Hz) following fatiguing contractions. While traditionally assessed using isometric contractions, the effect of PLFFD during dynamic contractions is much less explored. The purpose was to assess PLFFD at two loads (unloaded and 12.5% of maximal voluntary contraction) during dynamic isotonic and isometric contractions following a fatiguing task. Eighteen participants (23.3 ± 1.6 years, 6 females) performed continuous, maximal isokinetic cycles of concentric and eccentric knee extension contractions until a 75% loss of concentric peak power. Percutaneous electrical stimulation of the quadriceps was used to assess PLFFD beginning at 30 minutes of recovery by comparing pre- and post-fatigue 20:50Hz ratios. The 20:50Hz ratio for isometric torque declined 15.6% (p<0.001), indicating PLFFD. The loaded dynamic isotonic 20:50 Hz power ratio was significantly more depressed than isometric torque (36.4%, p<0.001), but there was no difference in the relative decline between the unloaded and isometric conditions (22.9%, p=0.57). Furthermore, the 20:50Hz isotonic velocity ratio was depressed with both loads (unloaded, 12.9% and loaded, 34.4% decrease, both p < 0.001) and this decline was greater than concentric torque in the loaded condition (34.4% and 7.4% decrease, respectively, p < 0.001). Therefore, the larger decline in the power ratios was due to the combined deficits in both torque and velocity, indicating that during PLFFD the impairment of isotonic power is greater than isometric torque, which is further impaired against a moderate (12.5%) load.