Influence of background vagal C-fiber activity on eupneic breathing pattern in anesthetized dogs.

In 19 dogs anesthetized with xylazine and alpha-chloralose, we examined the influence of background vagal C-fiber activity on the breathing pattern using a modified perineural capsaicin treatment. In seven dogs, we tested the efficacy of this treatment by recording compound action potentials before and after capsaicin application. In the remaining 12 dogs, we examined the effect of vagal perineural capsaicin on the Hering-Breuer expiratory facilitatory inflation reflex, pulmonary chemoreflex, and breathing pattern (tidal volume and expiratory and inspiratory times). Neither the peak height nor integral of the A wave of the compound action potential was significantly affected. However, the peak height and integral of the C wave of the compound action potential were significantly affected. However, the peak height and integral of the C wave of the compound action potential were significantly reduced. The myelinated fiber-initiated Hering-Breuer reflex remained intact after perineural capsaicin, but the C-fiber-initiated pulmonary chemoreflex was abolished. Perineural capsaicin increased tidal volume (0.399 +/- 0.031 to 0.498 +/- 0.058 liter; P < 0.05), expiratory time (3.62 +/- 0.31 to 4.82 +/- 0.68 s; P < 0.05), inspiratory time (1.49 +/- 0.12 to 1.72 +/- 0.17 s; P < 0.10) and total time per breath (5.11 +/- 1.08 to 6.54 +/- 0.82 s; P < 0.05). We conclude that background vagal C-fiber activity exerts an inhibitory effect on tidal volume and an excitatory effect on breathing frequency.

Role of airway receptors in altitude-induced dyspnea.

PURPOSE: The purpose of this study was to examine the role of airway receptors in respiratory-related sensations after ascent to altitude. METHODS: Ratings of respiratory-related sensations, perceived exertion and acute mountain sickness, heart rate, and peripheral oxygen saturation were recorded at rest and exercise in male and female subjects who had inhaled either aerosolized saline or saline with tetracaine after acute ascent to an altitude of 3500 m and after prolonged acclimatization of 18 d at altitudes between 4000 and 5000 m. RESULTS: Tetracaine had no effect on respiratory-related sensations at altitude either at rest or during exercise, and male and female subjects experienced similar respiratory-related sensations. Sensations of rapid breathing were experienced at rest after acute exposure to 3500 m as compared with sea level, but not after acclimatization to 5000 m. Sensations of rapid breathing, air hunger, and heavy breathing were experienced during exercise after acute and prolonged altitude exposure as compared with sea level, with a sensation of chest tightness experienced at 3500 m and a sensation of gasping experienced at 5000 m. CONCLUSION: These results suggest that airway afferents play no role in the respiratory-related sensations experienced by male and female subjects either during acute ascent to altitude or after prolonged acclimatization at altitude.

Increased pain tolerance as an indicator of return to work in low-back injuries after work hardening.

OBJECTIVE: This study examined retrospective data from a multidisciplinary work-hardening program that compared patients who did and did not return to work after low-back injury. The objective of this study was to identify differences between these groups to better guide work-hardening programs and return-to-work decisions. METHOD: Retrospective data from patients with low-back injuries (n = 115) who participated in a northern California work-hardening program were analyzed. Using two-way analysis of variance, male and female patients who did and did not return to work were compared. RESULTS: No significant differences were found between men and women for any of the variables studied. Patients who did and did not return to work were not significantly different in age, length of injury, and subjective pain at the beginning or end of the work-hardening program or in activity tolerance (p = .08). Patients who returned to work perceived a significantly (p < or = . 05) greater improvement in pain tolerance by the end of the work-hardening program than those who did not return to work. CONCLUSION: The results of this study suggest that rehabilitation emphasis should not be placed on the reduction of subjective pain but, rather, on strategies to cope with existing pain while improving functional ability.

Analysis of volatile compounds in exhaled breath condensate in patients with severe pulmonary arterial hypertension.

BACKGROUND: An important challenge to pulmonary arterial hypertension (PAH) diagnosis and treatment is early detection of occult pulmonary vascular pathology. Symptoms are frequently confused with other disease entities that lead to inappropriate interventions and allow for progression to advanced states of disease. There is a significant need to develop new markers for early disease detection and management of PAH. METHODOLGY AND FINDINGS: Exhaled breath condensate (EBC) samples were compared from 30 age-matched normal healthy individuals and 27 New York Heart Association functional class III and IV idiopathic pulmonary arterial hypertenion (IPAH) patients, a subgroup of PAH. Volatile organic compounds (VOC) in EBC samples were analyzed using gas chromatography/mass spectrometry (GC/MS). Individual peaks in GC profiles were identified in both groups and correlated with pulmonary hemodynamic and clinical endpoints in the IPAH group. Additionally, GC/MS data were analyzed using autoregression followed by partial least squares regression (AR/PLSR) analysis to discriminate between the IPAH and control groups. After correcting for medicaitons, there were 62 unique compounds in the control group, 32 unique compounds in the IPAH group, and 14 in-common compounds between groups. Peak-by-peak analysis of GC profiles of IPAH group EBC samples identified 6 compounds significantly correlated with pulmonary hemodynamic variables important in IPAH diagnosis. AR/PLSR analysis of GC/MS data resulted in a distinct and identifiable metabolic signature for IPAH patients. CONCLUSIONS: These findings indicate the utility of EBC VOC analysis to discriminate between severe IPAH and a healthy population; additionally, we identified potential novel biomarkers that correlated with IPAH pulmonary hemodynamic variables that may be important in screening for less severe forms IPAH.

Contribution of vagal afferents to breathing pattern in rats with lung fibrosis.

In anesthestized male Wistar rats with bleomycin-induced lung fibrosis we examined the influence of lung vagal non-myelinated and myelinated afferents in setting breathing pattern. Fourteen days after intratracheal instillation of bleomycin, lung compliance, total lung capacity (TLC) and inspiratory capacity were reduced while functional residual capacity and residual volume were increased. Baseline tidal volume (VT) was decreased and frequency (fR) increased in the bleomycin treated rats compared with controls. Selective vagal C-fiber blockade did not affect fR or VT in any group. Vagotomy resulted in an increase in VT and decrease in fR in both groups with the percent increase in VT/TLC and decrease in fR being significantly greater in the bleomycin rats compared with controls. Vagotomy also attenuated the significantly elevated PCO2 in the bleomycin treated rats suggesting that bleomycin-induced alterations in breathing pattern contribute to blood gas abnormalities. We conclude that vagal myelinated afferents contribute to the rapid shallow breathing in bleomycin treated rats.

Interaction of vagal lung afferents with inhalation of histamine aerosol in anesthetized dogs.

In seven alpha-chloralose anesthetized dogs we examined the contribution of lung afferents to the rapid, shallow breathing induced by inhalation of 10 breaths of histamine aerosol. In four spontaneously breathing dogs, the inhalation of histamine caused an increased respiratory frequency, decreased tidal volume, and decreased dynamic lung compliance. Selective blockade of pulmonary C-fibers abolished a reflex-induced increase in respiratory frequency but did not significantly affect the reductions in tidal volume or lung compliance. Terbutaline treatment in combination with C-fiber blockade abolished the reductions in tidal volume and lung compliance induced by histamine. In three separate alpha-chloralose anesthetized, open-chest, mechanically ventilated dogs, we recorded an increase in the inspiratory activity of rapidly adapting pulmonary stretch receptors (RARs) induced by the inhalation of histamine aerosol. Selective C-fiber blockade abolished histamine-induced increases in RAR activity while only partially attenuating reductions in lung compliance. We conclude that the increase in RAR activity induced by histamine depends on intact C-fibers and not on a direct effect of histamine on RARs or an indirect effect of histamine reducing lung compliance. In addition, our data illustrate the multiple interactions that occur between the various vagal afferents and their roles in the reflexes induced by histamine inhalation.

Pirfenidone attenuates bleomycin-induced changes in pulmonary functions in hamsters.

The antifibrotic potential of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) was examined in a single intratracheal bleomycin dose hamster model of pulmonary fibrosis. Bleomycin-induced fibrosis and the effectiveness of pirfenidone treatment were assessed by measuring pulmonary functions (Cqst, TLC, VC, IC, FRC, RV) and the level of hydroxyproline in whole lung homogenates. Thirty-five male golden Syrian hamsters were randomized into four experimental groups: saline instilled and fed a control diet of rat chow (SCD, n = 8); saline instilled and fed the control diet containing 0.5% (w/w) pirfenidone (SPD, n = 8); bleomycin instilled and fed the control diet (BCD, n = 7); and bleomycin instilled and fed the control diet containing 0.5% pirfenidone (BPD, n = 10). Twenty-one days following bleomycin instillation Cqst/TLC, TLC, VC, and IC were significantly reduced and total lung hydroxyproline levels were significantly increased in the BCD and BPD groups as compared with the SCD and SPD groups, respectively. Pirfenidone ingestion significantly attenuated these bleomycin-induced pertubations in pulmonary functions and lung hydroxyproline levels (BCD versus BPD). The data obtained in this study provide evidence of the benefical effects of pirfenidone in the hamster model of bleomycin-induced pulmonary fibrosis both at the functional and biochemical level.

Pulmonary vagal reflexes and breathing pattern are not altered in elastase-induced emphysema in rats.

The role of nonmyelinated and myelinated vagal afferents in pulmonary reflexes and breathing pattern was examined in elastase-treated emphysemic rats. Fourteen to 17 days after intratracheal instillation of 1 IU/gm of porcine pancreatic elastase or 0.5 mL of saline, elastase-treated rats had a decreased alveolar surface area to volume of parenchyma (Sv) (42.44 +/- 1.7 vs. 31.51 +/- 1.1 mm2/mm3), increased quasistatic compliance (QSC) (1.05 +/- 0.06 vs. 1.25 +/- 0.09 mL/cm H2O), functional residual capacity (FRC) (4.31 +/- 0.10 vs. 5.88 +/- 0.37 mL), residual volume (RV) (3.02 +/- 0.14 vs. 4.27 +/- 0.31 mL), and total lung capacity (TLC) (14.04 +/- 0.28 vs. 15.58 +/- 0.54 mL). There were no changes in the strength of the pulmonary chemoreflex, the strength of the Hering-Breuer inflation reflex, or breathing pattern before or after vagal perineural capsaicin treatment (VPCT) or vagotomy. There were, however, significant negative correlations between Sv and TLC, FRC and RV, and a near significant (p < .09) negative correlation between Sv and QSC, but no significant correlations between Sv and indices of either the pulmonary chemoreflex or Hering-Breuer inflation reflex. The results indicate that pulmonary vagal nonmyelinated and myelinated reflex activity and breathing pattern are not affected by elastase-induced emphysema in rats.

Effect of diet-ingested pirfenidone on pulmonary function, cardiovasculature and blood gas measurements in rats.

Pirfenidone is an antifibrotic drug that we have shown attenuates the increase in collagen buildup in hamsters exposed to bleomycin, in turn reducing pulmonary function and blood gas decrements seen in this model of interstitial pulmonary fibrosis. The systemic effects of pirfenidone ingestion, however, are unknown. We examined the effect of diet-ingested pirfenidone on pulmonary function, systemic and pulmonary cardiovasculature and blood gas measurements, breathing pattern and lung hydroxyproline content in rats fed either a control diet or a diet containing 0.5% pirfenidone. Residual volume was higher and expiratory reserve volume lower in the pirfenidone group, with no change in functional residual capacity. Tidal volume was also lower in the pirfenidone group, with no change in the overall level of ventilation. There was a trend toward a reduced hydroxyproline content and an increased lung compliance in the pirfenidone group. There were no differences in systemic or pulmonary pressures, cardiac output, stroke volume, heart rate, pH or blood gases between the two groups. These data indicate that pirfenidone has few systemic side-effects but may have a mild effect on the basal level of lung collagen content with resulting clinical changes in some pulmonary function measurements and changes in breathing pattern.

Lung vagal afferent activity in rats with bleomycin-induced lung fibrosis.

Bleomycin treatment in rats results in pulmonary fibrosis that is characterized by a rapid shallow breathing pattern, a decrease in quasi-static lung compliance and a blunting of the Hering-Breuer Inflation Reflex. We examined the impulse activity of pulmonary vagal afferents in anesthetized, mechanically ventilated rats with bleomycin-induced lung fibrosis during the ventilator cycle and static lung inflations/deflations and following the injection of capsaicin into the right atrium. Bleomycin enhanced volume sensitivity of slowly adapting stretch receptors (SARs), while it blunted the sensitivity of these receptors to increasing transpulmonary pressure. Bleomycin treatment increased the inspiratory activity, while it decreased the expiratory activity of rapidly adapting stretch receptors (RARs). Pulmonary C-fiber impulse activity did not appear to be affected by bleomycin treatment. We conclude that the fibrosis-related shift in discharge profile and enhanced volume sensitivity of SARs combined with the increased inspiratory activity of RARs contributes to the observed rapid shallow breathing of bleomycin-induced lung fibrosis.