Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension

Tumor necrosis factor (TNF)-alpha is a key proinflammatory cytokine that is thought to be important in the development of pulmonary fibrosis, whereas its role in pulmonary emphysema has not been as thoroughly documented. In the present study, TNF-alpha was overexpressed in alveolar type II cells under the control of the human surfactant protein C promoter. In this report, we further characterized the pulmonary abnormalities and provided a physiological assessment of these mice. Histopathology of the lungs revealed chronic inflammation, severe alveolar air space enlargement and septal destruction, and bronchiolitis. However, pulmonary fibrosis was very limited and only seen in the subpleural, peribronchiolar, and perivascular regions. Physiological assessment showed an increase in lung volumes and a decrease in elastic recoil characteristic of emphysema; there was no evidence of restrictive lung disease characteristic of pulmonary fibrosis. In addition, the mice raised in ambient conditions in Denver developed pulmonary hypertension. Gelatinase activity was increased in the lavage fluid from these lungs. These results suggest that in these mice TNF-alpha contributed to the development of pulmonary emphysema through chronic lung inflammation and activation of the elastolytic enzymes but by itself was unable to produce significant pulmonary fibrosis.     

Corticosteroids and surfactant increase lung volumes and decrease rupture pressures of preterm rabbit lungs

We measured the effects of corticosteroids and surfactant individually and in combination on lung pressure-volume relationships, rupture pressures, and rupture volumes. Pregnant does were injected with betamethasone (0.1 mg/kg per day im) or vehicle on days 24 and 25 of gestation, and fetal rabbits were delivered on days 26 and 27. Natural surfactant (50 mg/kg body wt) was instilled intratracheally into half of the lungs after tracheotomy. After nine cycles of inflation with air to 40 cmH2O and deflation, air pressure-volume curves were measured. Then the lungs were filled with air to rupture, and rupture volume and pressure were recorded. Both corticosteroids and surfactant caused an increase in maximal lung volumes (P less than 0.01) and a decrease of lung rupture pressures (P less than 0.01) compared with controls. The effects of corticosteroids plus surfactant on lung volumes were the sum of each effect individually, but rupture pressures were the same as those for corticosteroids or surfactant alone. Surfactant, in addition, caused an increase in lung stability at deflation, an effect that was not evident in the corticosteroid-treated groups. Measurements of saturated phosphatidylcholine in alveolar washes and lung tissue indicated comparable values in the corticosteroid and control groups. We conclude that changes in static properties and rupture pressures presumably reflect changes in lung structure caused by corticosteroids that are independent of a corticosteroid effect on surfactant pool sizes.     

Retention of lung distension information in pump cell spike trains

Respiratory control requires feedback signals from the viscera, including mechanoreceptors and chemoreceptors. We previously showed that typical pulmonary stretch receptor (PSR) spike trains provide the central nervous system with approximately 31% of the theoretical maximum information regarding the amplitude of lung distension. However, it is unknown whether the spatiotemporal convergence of many PSR inputs onto second-order neurons (e.g., pump cells) results in more, or less, information about the stimulus carried by second-order cell spike trains. We recorded pump cell activity in adult, anesthetized, paralyzed, artificially ventilated rabbits during continuous manipulation of ventilator rate and volume to test the hypothesis that less information is carried by spike trains of individual pump cells than PSRs. Using previously developed analytic methods, we quantified the information carried by the pump cell spike trains and compared it with the same values derived from PSR data. Our results provide evidence that rejects our hypothesis: pump cells as a group did not carry significantly less information about the lung distension stimulus than PSRs, although that trend was implied by the data. By comparing the response variances with the theoretical minimum, we discovered that the trend toward information loss depends on response strength, with higher mean responses associated with larger response variances in pump cells than in PSRs. Thus spatiotemporal integration may result in information loss within certain analytic/stimulus parameters, but this is counterbalanced by the consistency of pump cell responses during brief integration times and/or low stimulus amplitudes, resulting in retention of total information.     

Lung volumes and respiratory mechanics in elastase-induced emphysema in mice

Absolute lung volumes such as functional residual capacity, residual volume (RV), and total lung capacity (TLC) are used to characterize emphysema in patients, whereas in animal models of emphysema, the mechanical parameters are invariably obtained as a function of transrespiratory pressure (Prs). The aim of the present study was to establish a link between the mechanical parameters including tissue elastance (H) and airway resistance (Raw), and thoracic gas volume (TGV) in addition to Prs in a mouse model of emphysema. Using low-frequency forced oscillations during slow deep inflation, we tracked H and Raw as functions of TGV and Prs in normal mice and mice treated with porcine pancreatic elastase. The presence of emphysema was confirmed by morphometric analysis of histological slices. The treatment resulted in an increase in TGV by 51 and 44% and a decrease in H by 57 and 27%, respectively, at 0 and 20 cmH(2)O of Prs. The Raw did not differ between the groups at any value of Prs, but it was significantly higher in the treated mice at comparable TGV values. In further groups of mice, tracheal sounds were recorded during inflations from RV to TLC. All lung volumes but RV were significantly elevated in the treated mice, whereas the numbers and size distributions of inspiratory crackles were not different, suggesting that the airways were not affected by the elastase treatment. These findings emphasize the importance of absolute lung volumes and indicate that tissue destruction was not associated with airway dysfunction in this mouse model of emphysema.     

Changes in airway length after unilateral pneumonectomy in weanling ferrets

We have previously shown that airway cross-sectional area increases 15-20% after pneumonectomy in weanling ferrets by measuring bronchial casts. We have now reanalyzed these same casts to quantitate changes in airway length after pneumonectomy. In each cast the distance from each of 120 airways to the terminal bronchiole along its axial pathway was measured. The relationship between the logarithm of this distance and that of the fraction of the lobe subtended by an airway could be described by a quadratic equation with a correlation coefficient greater than 0.85. Subsegmental and more distal airways of postpneumonectomy animals were 33-47% longer than those of controls. Overall the main axial pathway of airways in the left lower lobes was 12% longer in operated animals, but this increase was primarily accounted for by an increase in the length of the more peripheral airways. Central airways were little if any longer in operated animals. After pneumonectomy in weanling ferrets, subsegmental and peripheral airway lengths increase to a greater degree than lung volume and airway cross-sectional area, whereas central airway lengths increase to a lesser extent if at all. The mechanisms responsible for this difference between central and intralobar compensatory airway growth are unknown.     

Improved lung preservation relates to an increase in tubular myelin-associated surfactant protein A

Background

Declining levels of surfactant protein A (SP-A) after lung transplantation are suggested to indicate progression of ischemia/reperfusion (IR) injury. We hypothesized that the previously described preservation-dependent improvement of alveolar surfactant integrity after IR was associated with alterations in intraalveolar SP-A levels.

Methods

Using immuno electron microscopy and design-based stereology, amount and distribution of SP-A, and of intracellular surfactant phospholipids (lamellar bodies) as well as infiltration by polymorphonuclear leukocytes (PMNs) and alveolar macrophages were evaluated in rat lungs after IR and preservation with EuroCollins or Celsior.

Results

After IR, labelling of tubular myelin for intraalveolar SP-A was significantly increased. In lungs preserved with EuroCollins, the total amount of intracellular surfactant phospholipid was reduced, and infiltration by PMNs and alveolar macrophages was significantly increased. With Celsior no changes in infiltration or intracellular surfactant phospholipid amount occurred. Here, an increase in the number of lamellar bodies per cell was associated with a shift towards smaller lamellar bodies. This accounts for preservation-dependent changes in the balance between surfactant phospholipid secretion and synthesis as well as in inflammatory cell infiltration.

Conclusion

We suggest that enhanced release of surfactant phospholipids and SP-A represents an early protective response that compensates in part for the inactivation of intraalveolar surfactant in the early phase of IR injury. This beneficial effect can be supported by adequate lung preservation, as e.g. with Celsior, maintaining surfactant integrity and reducing inflammation, either directly (via antioxidants) or indirectly (via improved surfactant integrity).     

Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets

A rotavirus was isolated from neonatal ferrets (Mustela putorius furo) with diarrhea at a large commercial farm. This virus is classified as an atypical rotavirus, probably belonging to the group C rotaviruses. This classification is based on the lack of the rotavirus group A common antigen and on its distinct dsRNA electropherotype pattern in polyacrylamide gels. The diarrheal disease was reproduced experimentally in neonatal ferrets.     

Proglumide fails to increase food intake after an ingested preload

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.