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Biomedical subjects

N J Gross

Publications and source records attributed to N J Gross.

At least 19 recordsLinked to original sources
PubMed1992

Requirements for extracellular metabolism of pulmonary surfactant: tentative identification of serine protease.

Pulmonary alveolar surfactant is secreted by the alveolar epithelium in the form of lamellar bodylike structures that evolve sequentially into tubular myelin and vesicular forms that can be separated by centrifugation. Using an in vitro procedure by which the extracellular metabolism of pulmonary surfactant can be mimicked, namely cyclic variation in surface area, we previously reported that serine protease activity, which we called "convertase," was required for the conversion of tubular myelin to the vesicular form. In the present studies we explored the biochemical requirements of this activity and sought the enzyme in alveolar products. Convertase activity has unusual requirements; in addition to being dependent on repetitive variations in surface area (cycling), it requires the presence of a high g fraction of lung secretions that is heat stable and not inhibitable by diisopropyl fluorophosphate (DFP) or alpha 1-antitrypsin, both typical serine protease inhibitors. The enzyme does not require calcium ions and has a pH optimum of 7.4. Convertase appears to be a component of surfactant itself because the ability of purified surfactant to convert to the vesicular form on cycling is impaired by pretreating it with DFP. A protein of Mr 75,000 that reacts with DFP and is heat sensitive was found in alveolar lavage, lamellar body preparations, and lung homogenate. It copurifies with lung surfactant in sucrose gradients. A similar DFP-reactive protein was observed in stable human neoplastic peripheral airway cell lines that express type II properties, suggesting that it may be a product of type II cells. We tentatively conclude that surfactant convertase is a 75,000 serine protease that is closely associated with surfactant phospholipid and that may be a product of alveolar type II cells.

Animals↗
PubMed1991

The influence of anticholinergic agents on treatment for bronchitis and emphysema.

Recent studies have shown that anticholinergic therapy is more effective than the most potent beta-adrenergic agents for chronic obstructive pulmonary disease. In the 3 years since it has been available to physicians in the United States, the quaternary anticholinergic drug ipratropium bromide (Atrovent) has had a considerable influence on clinical practice and the management of patients who have this disease. However, knowledge in this area is still incomplete. Questions remain as to the long-term effects of anticholinergic agents on the airways and, perhaps more important, on the natural progression of chronic obstructive pulmonary disease. Studies currently in progress will help determine the effect of prolonged therapy with anticholinergic agents on the progression and morbidity of lung disease.

Bronchitis↗
PubMed1991

Surfactant subtypes in experimental lung damage: radiation pneumonitis.

Radiation pneumonitis, a chronic form of adult respiratory distress syndrome (ARDS), is known to be associated with physiological and biophysical abnormalities of the surface element of the lungs suggesting an impairment of the surfactant system. The alveolar surfactant of mice with radiation pneumonitis was fractionated into subtypes on continuous sucrose density gradients to examine their relative amounts, composition, ultrastructure, surface activity, and turnover kinetics. The total phospholipid and protein contents of the alveolar lavage were increased. The proportions of high buoyant density subtypes (normally surface active) were increased about twofold and that of the low buoyant density subtype (not surface active) was decreased or absent. The buoyant densities, ultrastructure, and phospholipid compositions of the major surfactant subtypes were not significantly altered. The surface activity of the normally surface-active subtypes, when purified free of extraneous material, was close to those of normal controls. Turnover studies of the kinetics of surfactant subtype phospholipids suggested increased secretion of surfactant but a delay in the conversion of the heavier subtypes into their low-density product. Most of the heavier material appeared not to enter the lighter pool, in contrast to findings in control mice. It is concluded that in this form of ARDS the surfactant subtypes are qualitatively normal but that their surface activity is impaired, presumably by extraneous material in the alveoli, and that proportions of surfactant subtypes are radically altered by a combination of increased synthesis and decreased metabolism of the heavier subtypes.

Animals↗
PubMed1991

Inhibition of surfactant subtype convertase in radiation model of adult respiratory distress syndrome.

The accompanying paper [Am. J. Physiol. 260 (Lung Cell. Mol. Physiol. 4): L302-L310, 1991] showed that in the radiation pneumonitis model of adult respiratory distress syndrome (ARDS) there was an excess of the proximate, higher buoyant density subtypes of alveolar surfactant, and a decrease in the light buoyant density form. Because the surfactant subtypes normally evolve from the former to the latter a delay in the alveolar metabolism of surfactant could explain this disproportion. Three possible mechanisms of a delay in surfactant metabolism in radiation pneumonitis were explored using an in vitro model of surfactant subtype metabolism called "cycling". The first was that the surfactant of mice with radiation pneumonitis was intrinsically less capable of conversion to the light subtype. It was found, however, that the proximate forms of surfactant of mice with radiation pneumonitis were as capable of generating light subtype as those of control mice. The second was that there was a deficit in the serine protease activity, called "convertase", that mediates the conversion. But it was found that lungs of mice with radiation pneumonitis released convertase activity to the same extent as control lungs. The third was that an inhibitor of convertase activity was present in the alveoli. It was found that the alveolar lavage fluid of mice with radiation pneumonitis inhibited the conversion of exogenous surfactant by exogenous convertase. Moreover, it contained an 18-fold excess of antiprotease activity. The present data are interpreted as suggesting that an inhibitor in the alveolar space is responsible for the delay in surfactant subtype metabolism in radiation pneumonitis, resulting in the disproportion of surfactant subtypes in radiation pneumonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of some nonsteroidal anti-inflammatory agents on experimental radiation pneumonitis.

Corticosteroids have previously been found to be protective against the mortality of radiation pneumonitis in mice, even when given well after lethal lung irradiation. We explored the possibility that this effect was due to their well-known anti-inflammatory actions by giving various nonsteroidal inhibitors of arachidonate metabolism to groups of mice that had received 19 Gy to the thorax (bilaterally). Treatments of four cyclooxygenase inhibitors, one lipoxygenase inhibitor, and one leukotriene receptor antagonist, given by various routes in various doses, were commenced 10 weeks after irradiation or sham irradiation and continued throughout the period when death from radiation pneumonitis occurs, 11-26 weeks after irradiation. Each of the treatments had the appropriate effect on arachidonate metabolism in the lungs as assessed by LTB4 and PGE2 levels in lung lavage fluid. The principal end point was mortality. The 5-lipoxygenase inhibitor diethylcarbamazine and the LTD4/LTE4 receptor antagonist LY 171883 markedly reduced mortality in dose-response fashion. The effects of cyclooxygenase inhibitors were divergent; piroxicam and ibuprofen were marginally protective, indomethacin in all doses accelerated mortality, and aspirin reduced mortality in a dose-response fashion. These results suggest that the protective effect of corticosteroids in radiation pneumonitis can be tentatively attributed to their anti-inflammatory actions, and that nonsteroidal anti-inflammatory agents, particularly those that affect lipoxygenase products, may offer equal or better protection than corticosteroids against mortality due to radiation pneumonitis.

Acetophenones↗
PubMed1990

Serine proteinase requirement for the extra-cellular metabolism of pulmonary surfactant.

Pulmonary surfactant as lavaged from the alveoli exists in at least three structural subtypes, lamellar body-like, tubular myelin and vesicular forms that can be separated on the basis of their buoyant densities. Previous studies have suggested that surfactant is secreted in the lamellar body form and metabolized through the other subtypes in sequence. This metabolic sequence can be reproduced in vitro by cyclic expansion and contraction ('cycling') of the surface area of nascent surfactant at 38 degrees C. Cycling of nascent secretion, which is predominantly of lamellar body-like buoyant density, rapidly converted it to the buoyant density of tubular myelin and then to that of the vesicular subtype. We examined the role of proteinases in the conversion of nascent surfactant subtypes in vitro. Addition of metallo-, cysteine- and acid-proteinase inhibitors to the cycling mix did not inhibit the conversion of tubular myelin to vesicular subtype. However, a variety of serine proteinase inhibitors inhibited the formation of vesicular subtype. Their inhibitory effect was dose-related and most marked for alpha 1-antitrypsin where a concentration equal to that found in the alveolar fluid lining layer resulted in 50% inhibition of the generation of light subtype, suggesting physiological relevance. The enzyme(s) responsible for promoting the generation of light subtype was sedimentable and therefore presumably in particulate form. By differential centrifugation of lung secretions it was separable from alveolar macrophages and partially separable from surfactant itself. It has not been identified, nor has its substrate. We conclude that in vitro cycling provides a model for the study of alveolar surfactant metabolism and that the conversion of tubular myelin to vesicular forms of surfactant requires serine proteinase activity.

Animals↗
PubMed1990

Chronic obstructive pulmonary disease. Current concepts and therapeutic approaches.

The fifth leading cause of death in the United States, chronic obstructive respiratory conditions, cannot be cured but can be considerably ameliorated by appropriate management. Many patients with COPD have a combination of chronic bronchitis, asthma, and emphysema. While the damage due to emphysema is permanent, many of the pathophysiologic changes of asthma and bronchitis can be reversed to some extent, and such reversal should be a goal of therapy. Smoking cessation will help the patient more than any other medical treatment. Bronchodilator therapy is best given by inhalation from a metered dose inhaler and on a maintenance basis. Be sure to check inhaler technique. An anticholinergic agent, eg, ipratropium bromide, is probably most effective, but many patients prefer a beta 2-selective adrenergic agent. Xanthines are currently third choice but are very useful to cover nocturnal dyspnea. Corticosteroids are usually only used in acute exacerbations and then only for short courses. If prolonged use is required, however, the inhalation route minimizes side effects to which these patients are particularly prone. Antibiotics are also usually only used in exacerbations, but one can be liberal with them. Use the less expensive broad-spectrum options for ten days. Some clinicians believe that hydration is an effective expectorant. Mucolytic therapy is extensively used outside the United States. The appropriate role of mucolytic therapy in the treatment of bronchitis remains to be more fully explored. Low-flow oxygen is only used in the prevention or treatment of cor pulmonale when the PaO2 is persistently at or below 55, or with a rising hematocrit and right-sided cardiac changes. If used, oxygen is helpful only when given long term for at least 18 h per day, not on a prn basis. Cardiac glycosides are probably of little benefit, but diuretics have an important role in treatment of fluid retention. Pulmonary vasodilator therapy is still experimental, as is almitrine. Prophylaxis with pneumococcal vaccine and annual influenza vaccine is rational but has not been proven to be of value. Exercise and activity should be encouraged for all except those with frank congestive heart failure. The role of "breathing exercises" is currently being reevaluated. Surgery has almost no place in the management of COPD. Anesthesia often results in postoperative complications in this disease. Avoid all sedatives and tranquilizers.

Humans↗
PubMed1989

Surfactant subtypes in mice: characterization and quantitation.

Surfactant obtained by bronchoalveolar lavage of normal adult mice was separated into subtypes by a one-step centrifugation to equilibrium on continuous sucrose gradients. Mouse surfactant resolved in this way exists in three subtypes with similar phospholipid compositions. A "light" subtype of buoyant density 1.027 +/- 0.012 (SD) g/ml comprises 43 +/- 18% of the total alveolar lavage phospholipid, has little surface activity, and consists exclusively of small unilamellar vesicles. A "heavy" subtype of buoyant density 1.055 +/- 0.016 g/ml comprises 48 +/- 11% of the total, is surface active, and consists of small amounts of tubular myelin among large empty vesicles. A third component, called "ultraheavy," comprises 9 +/- 4% of the total alveolar lavage phospholipid, has a density of 1.072 +/- 0.020 g/ml, is surface active, and consists of large aggregates of tubular myelin associated with lamellar bodylike structures. Labeling studies suggested that the ultraheavy material was labeled first and was of the same density as purified lamellar bodies. These results are consistent with the view that, in mice, surfactant is secreted into the alveolar compartment in an ultraheavy form, which evolves into the heavy and light forms.

Animals↗
PubMed1989

Surfactant subtypes of mice: metabolic relationships and conversion in vitro.

Mouse alveolar surfactant can be separated by equilibrium centrifugation on continuous sucrose gradients into three subtypes which we call "ultraheavy", "heavy", and "light" on the basis of their buoyant densities. We examined their metabolic relationship by in vivo labeling studies and by physical manipulation, cycling the surface area in vitro in an attempt to convert one subtype into another. Labeling studies indicated rapid quantitative progression of surfactant through ultraheavy, heavy, and light subtypes in sequence. To mimic the in vivo conversion of subtypes in vitro we "cycled" the surface area of surfactant in plastic tubes. Newly secreted surfactant obtained from incubated lungs, as well as surfactant obtained by alveolar lavage and lamellar bodies, exhibited conversion of material from heavier to lighter subtypes. The conversion between subtypes was quantal and was dependent on cycling, temperature, and time. We conclude that the three subtypes are discrete forms of alveolar surfactant that evolve from one into another. Cycling may provide a means to study the mechanisms of their interconversion in vitro.

Animals↗
PubMed1989

Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study.

We performed a dose-response study of ipratropium bromide as a nebulized solution in patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind crossover format. Five doses from 0.05 to 0.6 mg of ipratropium bromide as a nebulized solution, the standard dose of ipratropium bromide by metered-dose inhaler, 40 micrograms, and placebo were given in random order on separate days. End points were the maximal increase in FEV1 and FVC, and the area under the FEV1 and FVC curves in the 8 h after administration of each of the seven treatments. Forty-two patients completed all seven study days. By each of the above end points for FEV1, 0.4 and 0.6 mg of nebulized ipratropium bromide achieved significantly more bronchodilatation than did each of the other treatments. These two doses were not significantly different from each other, suggesting that the optimal dose in this patient population is 0.4 mg. After this dosage, the FEV1 increased by 440 +/- 194 (mean +/- 1 SD) ml at peak effect between 1 and 2 h, and significant bronchodilatation persisted for 6.5 h. Ipratropium bromide by metered-dose inhaler (40 micrograms) was equivalent to approximately 0.1 mg by nebulized solution and achieved only 63 to 73% of the bronchodilatation achieved by optimal doses of the nebulized solution. In terms of FVC, all treatments with ipratropium were significantly better than with placebo. The area under the FVC curve was significantly greater after 0.4 and 0.6 mg of nebulized solution than after other treatments. No significant adverse experiences occurred with any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1989

Absence of tachyphylaxis to inhaled atropine in patients with chronic obstructive pulmonary disease.

A multicenter, 14-wk, double-blind, randomized, parallel group study of 60 patients with obstructive lung disease was performed to assess tachyphylaxis with inhaled atropine sulfate versus placebo. Forty patients completed the study; twenty-one were treated with placebo and nineteen were treated with atropine sulfate. Atropine and placebo groups were compared before and after inhaled atropine by spirometry at Weeks zero, 6, and 14. Medication side effects, other medication usage, and symptoms were recorded daily. Comparison of FEV1 response to atropine sulfate from baseline at Weeks zero, 6, and 14 did not show a statistically significant decrease. Inhaled atropine sulfate continued to be an effective bronchodilator in both placebo groups and atropine sulfate groups. There was no evidence of significant tachyphylaxis with atropine. Significant side effects in the atropine group when compared with placebo included dry mouth, dry skin, rapid heart rate, and nausea.

Administration, Inhalation↗
PubMed1989

Cholinergic bronchomotor tone in COPD. Estimates of its amount in comparison with that in normal subjects.

The use of anticholinergic bronchodilators in COPD is based on the reversal of cholinergic bronchomotor tone. There is little information about the magnitude of cholinergic tone in patients with COPD as compared with normal subjects. As an index of the amount of cholinergic tone we measured the maximum increase in FEV1 following administration of an optimal dose of the anticholinergic agent atropine methonitrate. The study included nine normal nonsmoking subjects, ten normal smokers and 22 subjects with mild to moderately severe COPD. We found that normal nonsmokers had smallest increases in FEV1 following atropine methonitrate administration. Responses of subjects with airway disease were progressively greater. Greatest responses occurred in the group of subjects with prebronchodilator FEV1 values less than 55 percent of predicted. The most plausible explanation for this is that cholinergic tone in COPD is increased in proportion to the severity of airway disease. Other explanations are possible.

Administration, Inhalation↗
PubMed1988

Ipratropium bromide.

Explore the source record for details and available documents.

Atropine Derivatives↗
PubMed1988

Recycling of surfactant in black and beige mice: pool sizes and kinetics.

Lung disaturated phosphatidylcholine (DSPC) turnover was investigated in normal C57 black and mutant beige mice; the latter have been postulated to have microtubular defects. Turnover experiments were performed on 117 black and 74 beige mice that were assayed for lamellar body-rich fraction (LB) and alveolar lavage fluid (AF) DSPC from 0.5 to 100 h after injection of [3H]glycerol. The data were analyzed by a program that derived the best-fit rate constants for an operator-chosen compartmental model. For black mice, a simple model with bidirectional exchange of DSPC between LB and AF compartments fitted the data almost as well as more complex models. This model yielded a turnover time of 5.9 h, a biological half-life of 16 h, and recycling of AF DSPC into LB of 47%. There was some evidence to suggest that DSPC might be degraded rather than recycled as a unit. For beige mice, the DSPC turnover time was 4.8 h, and its biological half-life was 40 h. The AF DSPC pool was smaller than in black mice, but the LB pool was larger. The bidirectional flux of DSPC between AF and LB was much greater than in black mice, the percent of recycling being 85. These data do not support a microtubular defect in beige mice, but the calculations for beige mice are based on a model of questionable validity.

Animals↗
PubMed1988

Experimental radiation pneumonitis. Corticosteroids increase the replicative activity of alveolar type 2 cells.

Corticosteroid administration during radiation pneumonitis in mice markedly improves the physiologic abnormalities and decreases mortality, an effect that has been attributed to the stimulation of surfactant synthesis and secretion by type 2 alveolar epithelial cells. In the present experiments we explored the effects of corticosteroids on the replicative activity of type 2 cells of lethally irradiated lungs at the height of the radiation reaction. The labeling index of type 2 cells of irradiated mice was increased threefold above that of sham-irradiated controls. Corticosteroids given continuously from 10 weeks after thoracic irradiation further increased the type 2 cell labeling index another threefold above that of irradiated untreated mice. The enhanced reproductive activity of type 2 cells following thoracic irradiation is seen as a protective response that is augmented by corticosteroids, whose effect may be both to improve the physiology of the alveolar surface and to maintain the population of alveolar epithelial cells. The bearing of this result on the controversial role of the type 2 cell as a target in radiation pneumonitis is discussed.

Adrenal Cortex Hormones↗
PubMed1988

The use of anticholinergic agents in the treatment of airways disease.

Anticholinergic agents are useful bronchodilators, the use of which should not be overlooked in patients with airways diseases. In patients with stable asthma, they are not first-line therapy but may be valuable as adjunctive therapy. In status asthmaticus they add to the bronchodilatation achieved by adrenergic therapy. Their principal role is in the maintenance therapy of chronic obstructive pulmonary disease. The newer synthetic forms, such as ipratropium bromide, are free of atropine-like side effects and have a wide therapeutic margin.

Autonomic Nervous System↗
PubMed1988

Protective effect of corticosteroids on radiation pneumonitis in mice.

We explored the protective effect of corticosteroids on the mortality of mice that received thoracic irradiation. Methylprednisolone, 100 mg/kg/week, given from 11 weeks after gamma irradiation of the thorax resulted in an increase in the LD50 (11-26 weeks) from 14.3 +/- 0.3 (mean +/- SE) Gy to 17.6 +/- 0.4 Gy, P less than 0.001, a protection factor of 1.2. Withdrawal of steroids at various times during the period of radiation pneumonitis resulted in accelerated mortality in the next 2-4 weeks, so that the cumulative mortality "caught up" with that of control animals by 4 weeks after steroid withdrawal. However, after the end of the usual period of pneumonitis withdrawal of steroids did not result in accelerated mortality, suggesting that the time when steroids are protective corresponds to the duration of pneumonitis. A smaller dose of steroids, 25 mg/kg/week, was found to be as protective as the larger dose used in the above experiments. The possibility that corticosteroids reduce mortality, even when given many weeks after radiation, may have important practical and theoretical implications.

Animals↗