Emphysematous Animals Research Articles

Compensatory lung growth after bilobectomy in emphysematous rats.

Lung volume reduction surgery (LVRS) is an option for emphysematous patients who are awaiting lung transplantation. LVRS reduces nonfunctional portions of lung tissues and favors the compensatory lung growth (CLG) of the remaining lobes. This phenomenon diminishes dyspnea and improves both the respiratory mechanics and quality of life for the patients. An animal model of elastase-induced pulmonary emphysema was used to investigate the structural and functional lung response after LVRS. Bilobectomy was performed six weeks after elastase instillation. Two weeks after bilobectomy, CLG effects were evaluated by lung mechanics and histomorphometric analysis. After bilobectomy, the emphysematous animals presented decreased mean linear intercepts, increased elastic fiber proportion, and increased alveolar surface density, total volumes of airspace, tissue and respiratory region and absolute surface area. We conclude that bilobectomy promoted CLG in emphysematous animals, resulting in alveolar architecture repair.

Early changes of lung function and structure in an elastase model of emphysema—a hyperpolarized3He MRI study

Early changes of lung function and structure were studied in the presence of an elastase-induced model of emphysema in 35 Sprague-Dawley rats at mild (5 U/100 g) and moderate (10 U/100 g) severities. Lung ventilation was measured on a regional basis (at a planar resolution of 3.2 mm) by hyperpolarized 3He MRI at 5 and 10 wk after model induction. Subsequent to imaging, average alveolar diameter was measured from histological slices taken from the centers of each lobe. Changes of mean fractional ventilation, mean linear intercept, and intrasubject heterogeneity of ventilation were studied during disease progression. Mean fractional ventilation was significantly different between healthy controls (0.23 +/- 0.04) and emphysematous animals at both time points in the 10-unit group (0.06 +/- 0.02 and 0.12 +/- 0.05, respectively). Changes in average alveolar diameter were not statistically observable until the 10th wk between healthy (37 +/- 10 microm) and emphysematous rats (73 +/- 25 and 95 +/- 31 microm, for 5 and 10 units, respectively). Assessment of function-structure correlation suggested that the majority of the decline in fractional ventilation occurred in the first 5 wk, while enlargement of alveolar diameters appeared primarily between the 5th and 10th wk. A thresholding metric, based on the 20th percentile of fractional ventilation over the entire lung, was utilized to detect the onset of the disease with confidence, independent of whether the regional ventilation measurements were normalized with respect to the delivered tidal volume and estimated functional residual capacity of each individual rat.

Morphogenesis of rat experimental pulmonary emphysema induced by intratracheally administered papain: changes in elastic fibres.

The ultrastructural changes of elastic fibres in emphysematous lungs have been studied in men, but few works exist on this topic in experimental emphysematous animals. In this paper, the morphogenesis of emphysema and alterations of the elastic fibres produced by the instillation of papain are described by light and electron microscopy. Wistar rats were instilled through the trachea with papain at a rate of 3 mg/100 g animal weight. The animals were sacrificed 12 h, 3 days, 10 days and 60 days after enzyme instillation. The "Mean Linear Intercept" (MLI), the "Number of fenestrations/respiratory units" (NF) the "Number of macrophages per mm of alveolar wall" (NM) and the "Number of respiratory unit/mm2" (RU), both in the control and experimental groups were studied. Two months after treatment, the experimental group showed a strong increase in the MLI (p<0.001) and NF (p<0.001), and a diminished number of RU (p<0.05) compared with the control group. Partial correlation analysis showed a positive correlation only between MLI and NF. Twelve hours after papain instillation an inflammatory response was observed, the elastic fibres were ruptured, while the microfibrilar component remained. New formations of eulanin elastic fibres were observed three days post papain instillation. After ten days the interalveolar oedema had disappeared and the elastic fibres were of normal morphology although irregular groups of strips of elastic fibres were evident. A mixed pattern of panlobular, centrilobular and normal lung zones were observed. Two months after papain instillation abundant accumulations of elastic fibres of irregular outline were observed associated to collagen fibres. In conclusion, the morphometric parameters studied showed a significant progression of the emphysema. The strong correlation between NF and MLI suggested that papain-induced emphysema is principally caused by breaches of the alveolar walls. The results seem to point to a very abnormal remodelling process associated with elastic fibre regeneration, although there were no signs of destruction of these new fibres formed in emphysematous rat lung induced by papain.

INHALATION ADMINISTRATION OF ALL-TRANS-RETINOIC ACID FOR TREATMENT OF ELASTASE-INDUCED PULMONARY EMPHYSEMA IN FISCHER 344 RATS

A past study demonstrated that all-trans-retinoic acid (ATRA) treatment by intraperitoneal injection in a rat model of elastase-induced emphysema caused tissue regeneration as evidenced by a decrease in alveolar size and lung volume and an increase in alveolar number. We postulated that treatment with this retinoid by nose-only inhalation exposure would be a more efficient means of targeting damaged lung tissue. Emphysema was induced in male Fischer 344 rats by intratracheal instillation of pancreatic elastase (0.5 IU/g body weight). Four weeks after elastase instillation, animals were treated once daily, 4 days/week, for 3 weeks by exposing them nose-only to aerosolized ATRA (target concentration-time of 3000 or 15,000 mg-min/m3) or by injecting them intraperitoneally with ATRA in cottonseed oil (0.5 or 2.5 mg/kg). Based on estimates of particle deposition in the respiratory tract, inhalation doses were chosen to be consistent with injected doses. Lungs were fixed by inflation with formalin (constant pressure for 6 hours followed by >48 hours of immersion) and were embedded in paraffin. Sections were evaluated by histopathology and stereology. Inhalation exposure to ATRA at both aerosol concentrations caused significant elevations of ATRA in the lung, whereas only the high-dose injection treatment was associated with an elevation of lung ATRA. The mean ATRA concentration from lungs of rats in the high-dose inhalation exposure groups as measured by liquid chromatography–mass spectrometry was approximately 12-fold greater than that of high-dose injection-treated rats. Elastase instillation caused increased lung volumes, irregular alveolar air space enlargement, and fragmentation and attenuation of alveolar septa. Neither inhaled nor injected ATRA reduced the enlarged lung volumes associated with this emphysema model. Stereology demonstrated that alveolar air space enlargement in ATRA-treated rats was similar to that in sham-treated emphysematous animals. Thus, while inhalation treatment caused greater levels of the drug in lung tissue in comparison to that of injection-treated animals, treatment with ATRA by either route of administration did not cause a reversal of lung tissue damage in this model of elastase-induced emphysema.

Lung volume reduction surgery restores the normal diaphragmatic length-tension relationship in emphysematous rats

Objective: Improved respiratory muscle function is a major effect of a lung volume reduction surgery. We studied length adaptation in rat diaphragmatic muscle in an attempt to elucidate the mechanism by which diaphragmatic function improves after this controversial operation. Methods: We developed a model of elastase-induced emphysema and bilateral volume reduction through median sternotomy in rats. Five months after emphysema induction, maximum exchangeable lung volume was determined in intubated and anesthetized control animals and animals with emphysema. Costal diaphragmatic length was measured in vivo, and the length at which maximal twitch force is generated was determined on muscle strips in vitro. Also 5 months after elastase administration, another cohort underwent volume reduction or sham sternotomy. Five months after the operation, these animals were similarly studied. Results: Lung volume was increased in emphysematous rats versus control rats (50.9 ± 1.7 vs 45.4 ± 1.3 mL, P =.001). Lung volume was decreased in emphysematous animals that had undergone volume reduction versus sham sternotomy (44.7 ± 0.60 vs 49.4 ± 1.0 mL, P =.001). In situ diaphragm length (1.99 ± 0.04 vs 2.24 ± 0.07 cm, P =.001) and the length at which maximal twitch force is generated (2.25 ± 0.06 vs 2.48 ± 0.09 cm, P =.038) were shorter in emphysematous than control animals. After volume reduction, in situ diaphragm length (2.13 ± 0.06 vs 1.83 ± 0.02 cm, P <.001) and the length at which maximal twitch force is generated (2.50 ± 0.08 vs 2.27 ± 0.06 cm, P =.013) were longer than in animals undergoing sham sternotomy. Conclusions: In this experimental model of emphysema and lung volume reduction surgery, emphysema shortens the length at which maximal twitch force is generated and shifts the diaphragmatic length-tension curve to lower lengths; volume reduction returns the length at which maximal twitch force is generated toward normal and shifts the diaphragmatic length-tension curve back to longer lengths. This restoration toward normal physiology may enable the improvement in diaphragmatic function seen after lung volume reduction surgery. The mechanism by which these length adaptations occur merits further investigation. (J Thorac Cardiovasc Surg 2001;121:217-24)

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.

The comparative effects of elastase-induced emphysema on costal and crural diaphragm and parasternal intercostal muscle contractility.

Chronically, hyperinflated human subjects with chronic obstructive pulmonary disease and animals with experimentally induced emphysema generate greater than expected levels of transdiaphragmatic pressure at high lung volume because of adaptive changes in the length-tension relationship of the costal diaphragm. The ability to lower intrathoracic pressure during inspiration depends on the mechanical action of all the inspiratory muscles acting in concert. However, the effect of chronic hyperinflation on the mechanical action of inspiratory muscles other than the costal diaphragm remains unknown. This study compares the effect of chronic hyperinflation in the form of elastase-induced emphysema on the contractile properties of the three major inspiratory muscles of the hamster (i.e., the costal and crural diaphragm and parasternal intercostals). Muscles were studied in vitro 6 months after emphysema was induced by intratracheal injection of elastase. Saline-injected animals served as controls. TLC in the elastase-injected hamsters was significantly greater than in controls (12.5 +/- 0.8 ml versus 9.0 +/- 0.3 ml, p < 0.002). Maximal tetanic tension, time to peak tension, maximal velocity of shortening, and the force-velocity relationship differed among the three muscles but for any given muscle were similar in control and emphysematous animals. In contrast, the fiber length optimal for tension generation (Lo) not only differed across muscles but was significantly shorter in the costal diaphragm of emphysematous animals compared with control animals. However, Lo of the parasternal intercostal and crural diaphragm was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

In VivoandIn VitroLung Reactivity in Elastase-induced Emphysema in Hamsters

Although patients with chronic obstructive lung disease often show airway hyperresponsiveness to constrictor challenge, the mechanisms underlying this hyperreactivity are unknown. In this study, we tested whether the elastase-induced hamster model of emphysema and bronchial secretory cell metaplasia shows a similar hyperreactivity. Four weeks after intratracheal administration of 0.2 mg/100 g body weight porcine pancreatic elastase, the animals were anesthetized and ventilated with a constant tidal volume of 5 ml/kg. Changes in airway pressure (Paw) were monitored before and after intravenous challenge with 0.7 mg/kg acetylcholine (ACh). There was a significant decrease in baseline Paw from 5.7 +/- 0.6 cm H2O in control animals (n = 6) to 4.0 +/- 0.6 cm H2O in emphysematous animals (n = 6). The peak Paw response to the intravenous challenge, normalized to the baseline Paw, was 2.9 +/- 0.4 in control animals, but it was significantly increased in the emphysematous animals to 4.4 +/- 1.1. Trachea, bronchi, and parenchyma from these lungs were challenged with cumulative dose of ACh and KCl. Sensitivity of the trachea and bronchi to ACh challenge, assessed as the log ED50, did not show differences between the two groups. However, the emphysematous parenchyma showed greater sensitivity to ACh compared with the control parenchyma. Trachea and bronchi from emphysematous animals showed significantly decreased maximal contractility to challenge with both ACh and KCl. In contrast, the emphysematous parenchyma showed significantly greater maximal contractility. These findings were independent of the baseline passive tension. This increased responsiveness may relate to increased passive distensibility of the emphysematous parenchyma.

Staphylococcus aureus pneumonia in hamsters with elastase-induced emphysema--the virulence enhancing activity of mucin.

Staphylococcus aureus pneumonia was studied in hamsters with elastase-induced emphysema and in saline-treated controls. Emphysematous animals cleared endotracheally administered inocula of S. aureus in saline as rapidly as controls. After infection with S. aureus in 1% mucin, emphysematous animals had impaired clearance compared with controls; after infection with S. aureus in 5% mucin, emphysematous animals had decreased survival at 96 hr compared to controls (6/24 vs 15/24, P less than 0.01 Fisher's exact test). Bronchoalveolar lavage of uninfected elastase-treated hamsters yielded twice as many cells per animal as uninfected controls (P less than 0.0001, paired t test), and the cells contained a higher percentage of polymorphonuclear leukocytes (37.8% vs 3.8%, P less than 0.0001). Lavage cells from both groups of animals were equally efficient per cell at killing opsonized S. aureus in an in vitro bactericidal assay. Hamsters with elastase-induced emphysema were resistant to infection with S. aureus alone despite marked structural abnormalities in the lung, possibly due in part to increased numbers of resident phagocytic cells. After infection with S. aureus in mucin as a virulence enhancing factor emphysematous animals had impaired clearance and decreased survival compared to controls.

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.

Length-tension relationship of abdominal expiratory muscles: effect of emphysema.

The present study examined the active and passive length-tension relationship of the abdominal expiratory muscles in vitro during electrically stimulated contractions. Studies were performed on isolated strips of transverse abdominis and external oblique muscle from nine adult hamsters with normal lung function. The effect of chronic hyperinflation on the two muscles was assessed in eight hamsters with elastase-induced emphysema. In normal animals the maximal active tension per cross-sectional area (Po) was equal in the two muscles. The absolute muscle fiber length at which Po occurred (Lo) was less for the external oblique than the transverse abdominis and the length-tension curve operated at shorter fiber lengths. However, the change in tension produced by an increase or decrease in muscle length expressed in relative terms (i.e., as %Lo) was greater for the transverse abdominis than the external oblique. Mean total lung capacity of emphysematous animals was 198% of control. Po of the transverse abdominis and external oblique were the same in emphysematous and control animals. However, Lo and the length-tension curve of the transverse abdominis occurred at shorter fiber lengths in emphysematous animals because of a reduction in the number of sarcomeres in series along the fiber. The length-tension curve and the number of sarcomeres in the external oblique was the same in emphysematous and control animals. These results in normal animals indicate that the magnitude of the change in active and passive tension produced by a change in muscle length differs in the transverse abdominis and external oblique. Moreover, chronic hyperinflation of the thorax produced by elastase injection alters the length-tension relationships of some but not all the expiratory muscles.

Changes in chest wall structure and elasticity in elastase-induced emphysema

The present study examined the effects of elastase-induced emphysema on the structure and elasticity of the chest wall. Specifically, we examined the passive pressure-volume relationship of the intact chest wall in anesthetized animals and the stress-strain relationship of the isolated rib cage devoid of respiratory musculature. The structure of the isolated rib cage was assessed by measuring its circumferential, anterior-posterior, and transverse dimensions, the angles of articulation of the ribs at the costovertebral and sternochondral joints, and the length of the sternum and individual ribs. Studies were performed in 10 Syrian Golden hamsters, 26-27 wk after intratracheal injection of elastase, and 9 saline-injected hamsters that served as controls. Mean functional residual capacity of emphysematous animals was 239% of the value obtained in control animals. In emphysematous animals, the pressure-volume curve of the chest wall was shifted parallel and to the left of the curve obtained in controls. That is, at any given esophageal pressure, lung volume was significantly greater in emphysematous animals compared with controls, but the slope of the pressure-volume relationship was similar in the two groups. In the relaxed position, the circumference, anterior-posterior, transverse, and rostral-caudal dimensions of the thorax were significantly greater in emphysematous than control animals. Although the length of the thoracic spinal column was the same in both groups, the length of the ribs and sternum were greater in emphysematous animals and the angles of articulation of the ribs with the vertebrae and sternum were altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase in number and decrease in size of mitochondrial profiles in myocytes of the right ventricle of dogs with experimental emphysema.

An ultrastructural study of the myocardium in control dogs and in dogs with papain-induced emphysema of 6 months duration without signs of right ventricular hypertrophy was undertaken to determine the number, size, and relative volume of the mitochondria. In the right ventricle of the emphysematous dogs, the number of mitochondrial profiles was greater per unit area of tissue (46.18 +/- 1.28/100 micron 2 versus 41.20 +/- 1.60/100 micron 2, p less than 0.05), but the mitochondria were smaller in size (mean mitochondrial profile area: 0.39 +/- 0.01 micron 2 versus 0.46 +/- 0.02 micron 2, p less than 0.05; mean mitochondrial "diameter": 0.65 +/- 0.01 micron versus 0.71 +/- 0.02 micron, p less than 0.05) than in control dogs. A highly significant negative correlation was found in the right ventricle of control and emphysematous dogs between the number per unit area and the size (area) of the mitochondrial profiles (r = -0.92; p less than 0.001). The increase in number but decrease in size of the mitochondrial profiles resulted in an unchanged relative volume of mitochondria in the right ventricle of the emphysematous dogs. In the subendocardium and in the subepicardium of the left ventricle of the papain-treated dogs, these changes were smaller and did not reach significance. These ultrastructural changes in the myocardium of the emphysematous animals are considered to be a response to a situation of prolonged increase in work of the right ventricle and may represent an early stage of a developing right ventricular hypertrophy.

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)

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.

Diaphragm in emphysematous hamsters: sarcomere adaptability.

We investigated whether the shift in the diaphragmatic length-tension curve of emphysematous animals was due to changes in either sarcomere number or sarcomere length. In vitro length-tension characteristics of the diaphragm were evaluated in control and emphysematous hamsters. Emphysema was induced by a single endotracheal instillation of elastase. Functional residual capacity, measured by means of a plethysmograph, was about twice that measured in emphysematous animals compared with control animals. Small diaphragmatic bundles were isolated and evaluated for their length-tension characteristics. The length-tension curve of diaphragms from emphysematous animals was displaced toward the left. Maximal tetanic tensions were similar in both groups, whereas optimal bundle length was significantly decreased in the emphysematous animals. Sarcomere number and sarcomere length at optimal length were then calculated for the diaphragmatic bundles. The bundles from emphysematous animals were found to have a significantly reduced number of sarcomeres, as well as a significantly decreased sarcomere length at optimal compared with control values. The total number of sarcomeres were also found to be significantly negatively correlated with the animal's functional residual capacity. From these results, we conclude that the decrease in diaphragmatic length, seen with hyperinflation, is due mainly to a loss of sarcomeres and possibly to a small decrease in sarcomere length measured at optimal bundle length.

The effect of elastase-induced emphysema on diaphragmatic muscle structure in hamsters.

The structure of the diaphragm was examined in 46 adult Golden hamsters in which emphysema was induced by intracheal instillation of elastase (25 units per 100 g body weight) and compared with 51 control animals injected with saline. Diaphragmatic muscle mass, thickness, fiber length, composition, and cross-sectional area, as well as the number of sarcomeres in series along the length of the muscle, were examined. The volume of excised lungs (25 cm H2O inflation pressure) was significantly increased in emphysematous animals (163% of control; p < 0.001). Muscle mass, which was assessed from the weight (dry and wet), was not significantly different in the 2 groups, but in both groups, whole muscle mass correlated directly with body weight (r = 0.87). Muscle thickness increased and fiber length decreased in emphysematous hamsters compared with that in control animals (p < 0.001 for each comparison). Reduction in fiber length in emphysema appeared to be due at least in part to a reduction in the number of sar...

Effect of Elastase-induced Emphysema on the Force-generating Ability of the Diaphragm

The effect of emphysema on the ability of the diaphragm to generate force was examined in costal diaphragm muscle strips from 10 Golden hamsters killed 18 mo after intratracheal injection of pancreatic elastase in a dose producing hyperinflation (mean total lung capacity [TLC] = 163% of control) and generalized panacinar emphysema. 13 saline-injected normal animals served as controls. The time course of isometric tension and the effect of alterations in muscle fiber and sarcomere length on the isometric tension (T) generated in response to tetanizing electrical stimuli (length-tension [L-T] relationship) were examined. Elastase administration caused an increase in diaphragm muscle thickness and reduction in the length of costal diaphragm muscle fibers measured in situ. Emphysema significantly increased the maximum tetanic tension as a result of hypertrophy. Maximal tension corrected for increases in muscle cross-sectional area (T/cm(2)), however, was the same in emphysematous (E) and control (C) animals. Emphysema also shifted the muscle fiber L-T curve of the diaphragm but not of a control muscle, the soleus, toward shorter lengths. In contrast to the effects of E on the diaphragm muscle fiber L-T curve, the sarcomere L-T curve was the same in E and C. Since the length at which tension was maximal correlated closely with sarcomere number (r = 0.94; P < 0.001) reduction in the number of sarcomeres in series in muscles from emphysematous animals appeared to explain the shift in the muscle fiber L-T curve. We conclude that in elastase-induced emphysema adaptive changes both in diaphragm cross-sectional area and sarcomere number augment the force-generating ability of the diaphragm. We speculate that changes in sarcomere number compensate for alterations in muscle fiber length resulting from chronic hyperinflation of the thorax, while diaphragmatic muscle hypertrophy represents a response to changes in respiratory load and/or diaphragm configuration (LaPlace relationship).

The effect of oxygen on Cor pulmonale in experimental emphysema induced by elastase or elastase and beta-aminopropionitrile in hamsters.

Right ventricular hypertrophy in elastase-induced emphysema in the System hamster was assessed by either the weight of the right ventricle as a fraction of body-weight or by the ratio of the weight of the right to the left ventricle. Right ventricular hypertrophy accompanies elastase-induced emphysema and is more severe in hamsters injected with elastase while fed a diet containing 0.5% beta-aminopropionitrile (BAPN), a combination that causes more severe emphysema. Measurements of arterial blood oxygen pressures showed that emphysematous animals were hypoxemic. Treatment of emphysematous animals with 35% O2 either during the development of right ventricular hypertrophy or after it had developed produced measurable amelioration of the hypertrophy in those groups with the more severe emphysema (elastase plus BAPN diet) but did not completely prevent it. The oxygen had no effect on the severity of the emphysema measured morphometrically. These results indicate that the cor pulmonale in elastase-induced emphysema is probably multifactorial, but hypoxia appears to be one of the major factors.