Emphysematous Hamsters Research Articles

Proteasome inhibition improves diaphragm function in an animal model for COPD

Diaphragm muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality. Recent studies indicate that increased contractile protein degradation by the proteasome contributes to diaphragm weakness in patients with COPD. The aim of the present study was to investigate the effect of proteasome inhibition on diaphragm function and contractile protein concentration in an animal model for COPD. Elastase-induced emphysema in hamsters was used as an animal model for COPD; normal hamsters served as controls. Animals were either treated with the proteasome inhibitor Bortezomib (iv) or its vehicle saline. Nine months after induction of emphysema, specific force-generating capacity of diaphragm bundles was measured. Proteolytic activity of the proteasome was assayed spectrofluorometrically. Protein concentrations of proteasome, myosin, and actin were measured by means of Western blotting. Proteasome activity and concentration were significantly higher in the diaphragm of emphysematous hamsters than in normal hamsters. Bortezomib treatment reduced proteasome activity in the diaphragm of emphysematous and normal hamsters. Specific force-generating capacity and myosin concentration of the diaphragm were reduced by ~25% in emphysematous hamsters compared with normal hamsters. Bortezomib treatment of emphysematous hamsters significantly increased diaphragm-specific force-generating capacity and completely restored myosin concentration. Actin concentration was not affected by emphysema, nor by bortezomib treatment. We conclude that treatment with a proteasome inhibitor improves contractile function of the diaphragm in emphysematous hamsters through restoration of myosin concentration. These findings implicate that the proteasome is a potential target of pharmacological intervention on diaphragm weakness in COPD.

Experimental pulmonary infection and colonization of Haemophilus influenzae in emphysematous hamsters

Background Bacterial infection has been considered the main cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, experimental model of COPD exacerbation induced by Haemophilus influenzae infection was not available up to now. Furthermore, only a few studies on evaluation of antibiotics using an H. influenzae infection model in mice have been reported. The aim of this work was to evaluate the activity of moxifloxacin on experimental pulmonary infection and colonization of H. influenzae in emphysematous hamsters. Methods Pulmonary emphysema was developed by intratracheal instillation of porcine pancreatic elastase in golden hamsters, which were infected by agar-beads enclosing H. influenzae to establish animal models of AECOPD. Alterations of lung histopathology, inflammatory factor levels in plasma and bronchoalveolar lavage fluids (BALFs), viable cell counting of lung tissue were determined on different days after challenge and moxifloxacin administration. Results Lung bacterial counts of BALFs and homogenates were significantly higher in emphysematous hamsters than those in normal non-emphysematous animals from 1 to 3 weeks after intratracheal inoculation of bacterial agar-beads suspensions. Moreover, H. influenzae colonized and survived for a longer period of time in emphysematous lungs than in normal non-emphysematous lungs after challenge. Efficacy of 3-day intragastric administration of moxifloxacin was proved by reduction in pulmonary H. influenzae burden and alleviation of inflammatory responses on days 4, 8 and 21 post-inoculation. No planktonic bacteria were isolated from BALFs in the first week after moxifloxacin treatment, and bacterial load in lung tissue homogenates declined significantly. Nevertheless, after 3 weeks, bacterial load in BALFs and homogenates of emphysematous lungs recovered to a large quantity. Inflammation in lung tissue, including lung consolidation, hemorrhage, and neutrophils infiltration, was conspicuously improved after administration of moxifloxacin. Levels of inflammatory factors in plasma were significantly decreased on days 8 and 21 after treatment compared with that without drug therapy. Inflammatory factors in BALF were also reduced, among which IL-8 dropped down markedly in early stage. Conclusion Our results suggest that chronic bacterial infection and colonization is highly correlated with lung emphysematous lesions, which would be one of the important mechanisms for repeated attacks of acute exacerbations of chronic pulmonary diseases and uncertain efficacies of antibiotics.

Apoptosis and Id2 expression in diaphragm and soleus muscle from the emphysematous hamster

During chronic obstructive pulmonary disease (COPD) diaphragm and peripheral muscle weakness occur. Muscle remodeling and wasting may be a result of apoptosis and changes in muscle-specific transcription factors, such as MyoD, altering muscle-specific gene transcription and muscle regenerative capacity. To investigate this, we instilled under ketamine/xylazine anesthesia porcine elastase in the lungs of hamsters to induce emphysema. The emphysematous hamster is an accepted model for COPD. In the diaphragm and peripheral muscles we assessed the occurrence of apoptosis, and in the diaphragm and soleus also the expression of MyoD and inhibitor of differentiation protein 2 (Id2). There was no significant muscle atrophy in emphysematous hamsters. The mRNA levels of TNF-alpha and markers of apoptosis were significantly elevated in the diaphragm and soleus muscles during emphysema. This was accompanied by an increased presence of nucleosomes in the cytosol. Caspase 3 activity and the DNA-binding activity of the p65 subunit of NF-kappaB, however, were unaltered in all muscles. The protein expression of MyoD and Id2 were decreased and increased in the diaphragm and the soleus muscle, respectively. Thus, despite the absence of muscle atrophy in emphysematous hamsters, there was evidence of increased TNF-alpha expression, apoptosis, and altered muscle-specific transcriptional regulation as reflected by decreased MyoD and elevated Id2 levels at least in the soleus and diaphragm muscle. These alterations may impair the regenerative capacity of skeletal muscles and ultimately contribute to muscle wasting.

Mitochondrial function in diaphragm of emphysematous hamsters after treatment with nandrolone

Respiratory failure in patients with COPD may be caused by insufficient force production or insufficient endurance capacity of the respiratory muscles. Anabolic steroids may improve respiratory muscle function in COPD. The effect of anabolic steroids on mitochondrial function in the diaphragm in emphysema is unknown. In an emphysematous male hamster model, we investigated whether administration of the anabolic steroid nandrolone decanoate (ND) altered the activity of mitochondrial respiratory chain complexes in the diaphragm. The bodyweight of hamsters treated with ND was decreased after treatment compared with initial values, and serum testosterone levels were significantly lower in hamsters treated with ND than in control hamsters. No difference in the activity of mitochondrial respiratory chain complexes in the diaphragm between normal and emphysematous hamsters was observed. Treatment with ND did not change the activity of mitochondrial respiratory chain complexes in the diaphragm of both normal and emphysematous hamsters. In emphysematous hamsters, administration of ND decreased the activity of succinate:cytochrome c oxidoreductase compared with ND treatment in normal hamsters. We conclude that anabolic steroids have negative effects on the activity of succinate:cytochrome c oxidoreductase and anabolic status in this emphysematous hamster model.

Short-term influences of lung volume reduction surgery on the diaphragm in emphysematous hamsters.

With emphysema, diaphragm length adaptation results in shortened fibers. We hypothesize that passive diaphragm stretch occurring acutely after lung volume reduction surgery (LVRS) results in fiber injury. Bilateral LVRS was performed in emphysematous hamsters. Studies were performed 1 (D1) and 4 (D4) days after LVRS, and compared with sham-treated groups. Sarcolemmal rupture was evident in 10.9% of fibers in LVRS-D1 and reduced to 1.6% in LVRS-D4. Ultrastructural analysis revealed focal abnormalities in both LVRS-D1 and LVRS-D4 animals in over one-third of fibers. Myofibrillar disruption was not observed in sham-treated animals. Diaphragm insulin-like growth factor-I (IGF-I) was increased in LVRS-D4 compared with other emphysematous groups. Increased IGF-I immunoreactivity was localized to types IIA and I fibers. The abundance of the splice variant of IGF-I mRNA sensitive to muscle stretch (IGF-IEb) increased 3.2-fold in LVRS D-4 diaphragms, compared with emphysema-sham animals. The main form of IGF-I mRNA was unchanged. Marked force deficit was observed in the LVRS-D1 diaphragm, compared with emphysema-sham and emphysema (no surgery) animals. These data highlight a markedly compromised ventilatory pump acutely after LVRS. Acute fiber stretch predisposes to muscle fiber injury and may also be a necessary mechanotransductive stimulus for fiber remodeling as the diaphragm adapts to reduced lung volume.

Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters.

The aim of this study was to evaluate whether recombinant human insulin-like growth factor I (rhIGF-I) could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg.kg-1.day-1 im); and 3) EMP + T + IGF-I (600 microg/day by constant infusion). After 4 wk, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T but preserved with rhIGF-I infusion. DIA fiber proportions were similar among the groups. The cross-sectional areas of types I, IIa, and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacological influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative-feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.

Effects of emphysema on diaphragm microvascular oxygen pressure.

Pulmonary emphysema impairs lung and respiratory muscle function leading to restricted physical capacity and accelerated morbidity and mortality consequent to respiratory muscle failure. In the absence of direct evidence, an O2 supply-demand imbalance within the diaphragm and other respiratory muscles in emphysema has been considered the most likely explanation for this failure. To test this hypothesis, we utilized phosphorescence quenching techniques to measure mean microvascular PO2 (PO2m) within the medial costal diaphragm of control (C, n = 10) and emphysematous (E, elastase instilled, n = 7) hamsters. PO2m and mean arterial pressure (MAP) were measured in the spontaneously breathing anesthetized hamster at inspired O2 percentages of 10, 21, and 100, and across a range of mean MAPs from 40 to 115 mm Hg. At each inspired O2, diaphragm PO2m was significantly (p < 0.05) lower in E animals (10%: C, 19 +/- 3; E, 9 +/- 2; 21%: C, 32 +/- 2; E, 21 +/- 2; 100%: C, 60 +/- 8; E, 36 +/- 9 mm Hg). At 21% inspired O2, the PO2m decrease was correlated with reduced MAP in both C (r = 0.968) and E (r = 0.976) animals. We conclude that diaphragmatic PO2m (and therefore microvascular O2 content) is decreased in emphysematous hamsters reflecting a greater diaphragmatic O2 utilization at rest and a lower O2 extraction reserve. According to Fick's law, this lower PO2m will mandate an exaggerated fall in intramyocyte PO2, which is expected to accelerate muscle glycogen depletion and consequently fatigue. This provides empirical evidence in support of one possible mechanism for respiratory muscle failure in emphysema.

EVIDENCE FOR A REDUCED DIAPHRAGMATIC MICROVASCULAR PO2 IN EMPHYSEMA

507 Pulmonary emphysema impairs lung and respiratory muscle function leading to restricted physical capacity and accelerated morbidity and mortality consequent to respiratory muscle failure. In the absence of direct evidence, an O2 supply-demand imbalance within the diaphragm and other respiratory muscles in emphysema has been considered the most likely explanation for this failure. To test this hypothesis, we utilized phosphorescence quenching techniques to measure mean microvascular plasma PO2 (PO2dia, [Poole et al. J. Appl. Physiol. 79: 2050-2057, 1995 ]) within the medial costal diaphragms of control (C, n=5) and emphysematous (E, elastase instilled, n=6) hamsters. PO2dia, mean arterial pressure and blood gases were measured in the spontaneously breathing anesthetized hamster at inspired O2 concentrations of 10 and 21%. Arterial PO2 was decreased in the E hamsters at 21% (C, 90±13; E, 48±7 mmHg, P<0.05) and 10% (C, 55±8; E, 30±3 mmHg, P<0.05) inspired O2. At 21% inspired O2, PO2dia was significantly lower in the emphysema animals (C, 33±2; E, 22±3 mmHg, P<0.05). PO2dia decreased significantly at 10% inspired O2 in both C and E animals but remained lower in E (C, 19±3; E, 11±2 mmHg, P<0.05). We conclude that diaphragmatic microvascular plasma PO2 is decreased in emphysematous hamsters. According to Fick's Law, this will mandate a fall in intramyocyte PO2 thereby providing one possible mechanism for respiratory muscle failure in emphysema. Support: NIH HL-50306 and 17731.

Effects of anabolic steroids on diaphragm impairment induced by methylprednisolone in emphysematous hamsters.

This study was designed to investigate whether the administration of the anabolic steroid nandrolone decanoate is able to antagonize the loss in diaphragm function induced by long-term administration of a low-dose of methylprednisolone in emphysematous hamsters. Normal and emphysematous male hamsters were randomized to receive either saline or methylprednisolone 0.2 mg x kg(-1) x day(-1) for 9 months, with or without nandrolone decanoate 1 mg x kg(-1) x week(-1) i.m. during the final 3 months. Diaphragm contractile properties and myosin heavy chain composition were determined. Compared to control hamsters, the force generating capacity of isolated diaphragm strips decreased by approximately 12% in the emphysema group and by approximately 22% in the emphysema plus methylprednisolone group. Addition of nandrolone decanoate to the emphysema plus methylprednisolone hamsters significantly improved force generation. The atrophy of type IIa and IIx diaphragm fibres in the emphysema plus methylprednisolone group was completely reversed to the level of control hamsters by the addition of nandrolone decanoate. In conclusion, nandrolone decanoate in part reversed the loss in diaphragm force-generating capacity in emphysematous hamsters treated with methylprednisolone, and reversed type IIa and IIx fibre atrophy completely.

Long-term effects of clenbuterol on diaphragm morphology and contractile properties in emphysematous hamsters.

The aim of the present study was to investigate the effect of chronic long-term clenbuterol treatment (1 mg/kg subcutaneously twice a day for 12 wk) on diaphragm morphology and function in emphysematous (EH) and normal hamsters (NH). Clenbuterol increased body weight, diaphragm weight, and skeletal muscle weight in both EH and NH to a similar extent. In the diaphragm, clenbuterol significantly increased myosin heavy chain type I, IIa, and IIx muscle fiber cross-sectional areas by approximately 35-55% in both EH and NH. This response to clenbuterol treatment was not significantly different between EH and NH diaphragm. In EH, twitch force (Pt), maximal tetanic force, and force-frequency curve were significantly reduced compared with NH. In EH, clenbuterol increased Pt by approximately 10%, restoring Pt to NH level. A similar improvement was observed in the force-frequency characteristics. Clenbuterol did not alter contractile properties in NH. In conclusion, long-term clenbuterol treatment resulted in an increased size of all diaphragm muscle fiber types in both NH and EH. Clenbuterol completely abolished the reduced force generation induced by emphysema.

Myosin and actin filament lengths in diaphragms from emphysematous hamsters

In vitro studies of the diaphragm from emphysematous animals have, in some instances, shown an alteration in its sarcomere length-tension relationship and a decreased maximal specific tension. To our knowledge, it has never been determined whether such functional changes may be indicative of ultrastructural adaptations, e.g., changes in filament lengths and thus cross-bridge number. To address this, we compared filament lengths in diaphragms from hamsters in which emphysema was induced by endotracheal instillation of elastase (E) 5 mo before the hamsters were killed with those from control hamsters (C; saline instillation). Diaphragms were then fixed by vascular perfusion with buffered glutaraldehyde in situ at airway pressures set to approximate the physiological range of lung volumes from residual volume (RV) to total lung capacity (TLC). Ultrathin sections (50-70 nm) were taken parallel to the muscle fiber axis and examined by electron microscopy (x33,000). Sarcomere and filament length measurements were calibrated using an actin periodicity of 39 nm and an M-band width of 86 nm to correct for dimensional changes during preparation. Emphysema increased the change in lung volume from -20 to +25 cmH2O airway pressure (from RV to TLC) by approximately 88%, and the displacement volume of excised lung at 0 cmH2O airway pressure was increased by approximately 138% on average. Neither myosin (C = 1.592 +/- 0.027; E = 1.572 +/- 0.035 micron; P = 0.72) nor actin (C = 1.210 +/- 0.035; E = 1.221 +/- 0.014 micron; P = 0.76) filament lengths were affected by emphysema. Thus, filament length changes do not underlie the diaphragm functional adaptations observed previously in emphysema.

Diaphragm Structure and Function in Emphysematous Hamsters

OBJECTIVE: To determine if muscle fibre injury, reduced force output and fatigue of the diaphragm accompanied hyperinflation induced by experimental emphysema.DESIGN: Controlled and randomized.ANIMALS: Adult male golden Syrian hamsters: seven control and seven experimental emphysema hamsters were studied.INTERVENTIONS: Following anesthesia, experimental emphysema hamsters received a transtracheal injection of elastase. They also received injections of β‐aminopropionitrile every other day for five weeks. After five weeks, all hamsters we re anesthetized , and their diaphragm and lungs were excised.MAIN RESULTS: Measurements of the excised lungs showed an increased residual volume. functional residual capacity and total lung capacity in experimental emphysema hamsters. In vitro physiological study of diaphragm strips showed no difference in force output but a greater fatiguability during repetitive stimulation for 5 mins in experimental emphysema hamsters than in control hamsters. Histological examination did not show significant muscle injury in the diaphragm of experimental emphysema hamsters.CONCLUSION: The greater fatiguability and absence of muscle injury in the diaphragm of emphysematous hamsters may result from hyperinflation decreasing diaphragmatic load. Alternatively, muscle damage not detectable at the light microscopic level may have contributed to increased fatiguability of the diaphragm of experimental emphysematous hamsters.

Pulmonary vascular reactivity and hemodynamic changes in elastase-induced emphysema in hamsters

Changes in pulmonary hemodynamics and vascular reactivity in emphysematous hamsters were studied in an isolated lung preparation perfused at constant flow with blood and 3% dextran. Hamsters were treated with intratracheal porcine pancreatic elastase at 70 days of age, and experimental studies were conducted at 1, 3, and 8 mo after treatment. Baseline pulmonary arterial pressure in elastase-treated lungs was increased compared with saline-treated control lungs 1 mo after treatment, but this increase did not progress at 3 and 8 mo. Increases in pulmonary arterial pressure in elastase-treated lungs were temporally correlated with the morphological development of emphysema and right ventricular hypertrophy; both of these were evident at 1 mo after treatment and showed little change thereafter. Pressor responses to hypoxia and angiotensin II were not different between elastase-treated and control lungs at 1 and 3 mo. At 8 mo, however, pressor responses in emphysematous lungs to 0% O2 (but not to angiotensin II) were significantly increased. This was the result of a lack of the normal age-related fall in the hypoxic pressor response. Our results suggest that the right ventricular hypertrophy found in these emphysematous animals results from a chronically increased pulmonary vascular resistance. Furthermore, increases in pulmonary vascular resistance in the early development of emphysema are likely a result of the loss of vascular beds and supporting connective tissue.

Structure of abdominal muscles in the hamster: effect of elastase-induced emphysema.

The present study examined the effects of elastase-induced emphysema on the structure of the external oblique and transverse abdominis muscles and a non-respiratory muscle, the extensor digitorum longus. Muscle structure was assessed from the cross-sectional area (CSA) and percent of individual fiber types in histochemically stained sections and from the number of sarcomeres arranged in series along the length of individual fibers. Data were obtained in eight hamsters with emphysema and nine saline-injected controls. In the normal (control) animals the external oblique was thicker but contained fewer sarcomeres than the transverse abdominis. Fiber size was similar in the two muscles. In the transverse abdominis the percents of fast-glycolytic and fast-oxidative fibers were greater and smaller, respectively, than in the external oblique. Lung volume of emphysematous hamsters was 168% of control values (P less than 0.001). In emphysematous compared with control animals, the CSA of fast-twitch fibers in the external oblique and transverse abdominis was significantly reduced. Fiber length and sarcomere number were significantly decreased in the transverse abdominis but not in the external oblique in emphysematous hamsters. In contrast, fiber size and composition of the extensor digitorum longus was similar in emphysematous and control animals. These data indicate that cellular responses of the ventilatory muscles to chronic hyperinflation and altered thoracic geometry induced by emphysema are not present in limb skeletal muscle. We speculate that changes in fiber length and CSA of fast fibers in the abdominal expiratory muscles reflect responses to chronic alterations in the mechanics of breathing that may affect muscle load, length, or the pattern of activity.

Effect of low-level NO 2 chronic exposure on elastase-induced emphysema

The effect of chronic exposure to 2 ppm nitrogen dioxide (NO2) for 8 hr a day, 5 days a week, for 8 weeks was assessed in normal and emphysematous hamsters by measuring (1) lung morphometry (mean linear intercept [Lm] and internal surface area [ISA]), (2) lung mechanics (lung volume, compliance and coefficient of static deflation, pressure-volume curve fitted to an exponential equation), and (3) serum elastolytic activity and protease inhibitor capacity. Emphysema was induced by a single intratracheal injection of 6 IU porcine pancreatic elastase. Four groups of animals were used; Control, NO2-exposed, elastase-treated, and NO2-exposed postelastase. Our results show that NO2 exposure alone induced mild emphysematous lesions whose degree of severity estimated by morphometry increase in Lm and decrease in ISA. P less than 0.01) was of the same order as that of the lesions induced by 6 IU elastase. Exposure to 2 ppm NO2 enhanced elastase-induced emphysema (further increased Lm and further reduced ISA. P less than 0.01). By contrast, study of lung mechanics revealed no difference between the control and NO2-exposed groups or between the elastase-treated animals exposed to NO2 and those not so exposed. This apparent discrepancy between results of morphometry and lung mechanics may be due to the lower sensitivity of lung mechanics parameters and their consequent inability to reflect changes in the emphysematous lesions induced by elastase injection or 2 ppm NO2 inhalation. In vivo, serum elastolytic activity and protease inhibitor capacity were not modified in any group, indicating that either serum does not reflect the degree of protease inhibitor capacity in the alveolar spaces or chronic inhalation of low concentrations of NO2 is not sufficient to cause elastase/antielastase imbalance. Lastly, our results suggest that chronic exposure to 2 ppm NO2 may cause individuals with inherited or acquired emphysematous lesions to develop more severe emphysema.

The effect of SO 2 on the clearance of Listeria monocytogenes from the lungs of emphysematous hamsters

The effect of sulphur dioxide on the clearance of Listeria monocytogenes from normal and emphysematous hamsters was assessed by measuring the number of colony forming units recovered from whole lung homogenates. Continuous exposure to SO2 after intratracheal instillation of Listeria significantly altered the clearance of viable bacteria from the lungs of emphysematous but not normal hamsters. Preexposure of hamsters to SO2 for 2 weeks prior to respiratory infection had similar effects. The emphysematous hamsters exposed to SO2 had a lower average number of Listeria in the lungs after the first week of infection than control groups. This effect appears to result from the combined influence of the SO2, the Listeria infection, and the emphysematous condition within the lungs.

Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters.

Costal strips of diaphragmatic muscle obtained from animals with elastase-induced emphysema generate maximum tension at significantly shorter muscle fiber lengths than muscle strips from control animals. The present study examined the consequences of alterations in the length-tension relationship assessed in vitro on the pressure generated by the diaphragm in vivo. Transdiaphragmatic pressure (Pdi) and functional residual capacity (FRC) were measured in 22 emphysematous and 22 control hamsters 4-5 mo after intratracheal injection of pancreatic elastase or saline, respectively. In 12 emphysematous and 12 control hamsters Pdi was also measured during spontaneous contractions against an occluded airway. To allow greater control over muscle excitation, Pdi was measured during bilateral tetanic (50 Hz) electrical stimulation of the phrenic nerves in 10 emphysematous and 10 control hamsters. Mean FRC in the emphysematous hamsters was 183% of the value in control hamsters (P less than 0.01). During spontaneous inspiratory efforts against a closed airway the highest Pdi generated at FRC tended to be greater in control than emphysematous hamsters. When control hamsters were inflated to a lung volume approximating the FRC of emphysematous animals, however, peak Pdi was significantly greater in emphysematous animals (70 +/- 6 and 41 +/- 8 cmH2O; P less than 0.05). With electrophrenic stimulation, the Pdi-lung volume curve was shifted toward higher lung volumes in emphysematous hamsters. Pdi at all absolute lung volumes at and above the FRC of emphysematous hamsters was significantly greater in emphysematous compared with control animals. Moreover, Pdi continued to be generated by emphysematous hamsters at levels of lung volume where Pdi of control subjects was zero.(ABSTRACT TRUNCATED AT 250 WORDS)

Young hamsters are more resistant than adults to endotracheally instilled porcine pancreatic elastase.

We measured the physiologic and stereologic response to 0.1, 0.2, and 0.4 microgram of porcine pancreatic elastase instilled in a volume of 0.25 ml 0.9% NaCl/100 g body weight into the trachea of groups of young and adult hamsters. The young hamsters averaged 50 g and the adult hamsters 116 g in initial body weight. Twenty-one days after administration of elastase, lung volumes, static lung compliance, maximum expiratory flow, the whole section mean linear intercepts (MLI) were measured. The degree of emphysema increased in all animals as a function of dose. Examination of the lung volume and compliance dose-response characteristics indicated that young hamsters developed less physiologic change with increasing elastase dose than did adult hamsters. Maximum expiratory flow and whole section MLI dose-response were similar in the young and adult elastase-treated groups. However, the MLI in young hamsters treated with the 0.4 microgram elastase dose was decreased in the outer third of the lung compared to adult emphysematous hamsters. Also, mean airspace density relative to saline control values in young hamsters was double that found in adult hamsters treated with the 0.4 microgram elastase dose. Although serum alpha 1-globulin levels were equivalent in both young and adult normal hamsters, values normalized for lung elastin content were significantly increased in young animals. We conclude that young hamsters show less change in lung function as a function of elastase dose twenty-one days after elastase instillation. Possible reasons for this include an increased ratio of lung alpha 1-globulin/lung elastin in young hamsters, their continued ability to grow new alveoli, and age related differences in airway size favoring a central distribution of enzyme.

Histochemical and biochemical correlates of ventilatory muscle fatigue in emphysematous hamsters.

Histochemical and biochemical characteristics of the ventilatory muscles were evaluated in control and elastase-induced emphysematous hamsters. The emphysematous group was divided into sedentary and endurance-trained groups. Endurance training consisted of treadmill running, 1 h a day, 7 d a week. The experimental period lasted 24 wk. Histochemically, the diaphragm from the sedentary emphysematous hamsters revealed a selective fast fiber atrophy which was prevented by endurance training. Training also led to a hypertrophy of the slow, high oxidative fibers. The external intercostals from both emphysematous groups revealed an increased proportion of fast oxidative fibers at the expense of a decreased number of fast glycolytic fibers. However, the fast fibers in both emphysematous groups were significantly atrophied as compared with controls. The internal intercostals revealed no adaptive changes in either size or proportion distribution of the various fiber types. Biochemically, the diaphragm of the emphysematous animals had a significantly improved oxidative potential as measured by citrate synthase, and a reduced glycolytic capacity as indicated by phosphofructokinase activity, compared with controls. The magnitudes of the biochemical changes were similar in both emphysematous groups and were consistent for diaphragmatic samples taken from the costal and crural segments. The combined internal and external intercostals also underwent significant biochemical increases in their oxidative capacity. In addition, training of the emphysematous group led to an increased glycolytic potential of the intercostals.

Diaphragmatic Alterations in Sedentary and Exercised Emphysematous Hamsters

Diaphragmatic Alterations in Sedentary and Exercised Emphysematous Hamsters