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The cellular effects of irradiating the lungs are rleated to the histologic and clinical sequelae. The occurrence and severity of damage rare semiquantitatively related to the volume of lung irradiated, and the dose rate of irradiation. The clinical syndrome occurs in up to about 10% of patients and consists of an acute transient phase, radiation pneumonitis, usually occurring 6 to 12 weeks after radiation therapy. This is followed by clinical remission except in the most severe cases and gradula radiologic progression to the stage of radiation fibrosis over the next 6 to 12 months. Concommittant chemotherapy, repeat courses of radiation, and steroid wihtdrawal are exacerbating factors. Characteristic changes in pulmonary function and radiographic appearance are described, and management is reviewed.

The effect of cromolyn sodium on in vitro human lymphocyte viability and activation by phytohemagglutinin and PPD has been investigated in 24 subjects. The presence of cromolyn in the culture (10 mug/ml) significantly reduces the viability of lymphocytes at both 3 days and 5 days. This concentration is probably greater than that which would normally be present in the blood of patients receiving therapeutic amounts of cromolyn, but less than that to which pulmonary lymphocytes would be exposed following inhalation of cromolyn. Cromolyn in concentrations of 0.1 to 100 mug/ml has no effect upon thymidine uptake or viability of lymphocytes following phytohemagglutinin or PPD stimulation.

Mice received 2400 rads in two fractions to the thorax; 4 months later at a time when deaths began, mechanical and biochemical properties of the lungs were studied and compared to those of littermate controls. The principal mechanical change was a large increase in the elastance of the alveolar surface element and abnormal surface tension properties of the AF. Alveolar fluid phospholipid content and saturation were only minimally change; however the alveolar fluid contained a large excess of protein, possibly of circulatory origin. The latter may explain the fall in compliance of the alveolar surface and hence of the lung in radiation pneumonitis. A small increase in elastance of the lung tissue element was also found; this correlated with a decrease in lung volume and a small increase in lung hydroxyproline content. These changes may signify the early development of radiation fibrosis. Other features of this model are the frequent occurrence of pleural effusions and the presence of increased numbers of alveolar macrophages in the alveolar lavage.

A study of surfactant physiology and biochemistry was undertaken in mice who received varying doses of X-irradiation to the thorax. During the first 12 weeks after X-irradiation, the period which precedes radiation pneumonitis, there is an increase in the amount of DPC in both the lung and the alveolar surface lining layer. This increase begins about 7 days after irradiation, returns to control levels by 12 weeks, and coincides with a fall in the total number of AM's. Over-all synthesis of DPC in the lung and its transport to the alveolar surface, as determined by incorporation of 3H from glycerol and 14C from palmitate into PC in vivo, remained unchanged from control levels. These results may be explained in part by proliferation of type 2 pneumocytes following X-irradiation and by decreased removal of surfactant from the alveolar surface, possibly as a result of the depletion of the AM population. No changes in mechanical properties of the lung or in situ E tis or E surf occurred at this stage, nor were changes detected in the surface properties of the alveolar lavage fluid.

Lymphocytes from 12 normal subjects were stimulated in vitro with several concentrations of six commercial preparations of phytohemagglutinin and one column-purified preparation. All preparations produced activation profiles that were highly concentration dependent, with diminished activation at concentrations greater than the optimal concentration. The preparations differed markedly in their mitogenic capacities. Several concentrations of phytohemagglutinin should be employed when lymphocyte activation in vitro is studied as an index of cell-mediated immunity.

The size of the lung cancer problem and the dismal results of conventional therapy justify close attention to the possibilities of immunotherapy. Lung cancer patients, like other tumor patients, are often relatively immunosuppressed although an immune response directed against autochthonous tumor cells can usually be demonstrated. All conventional forms of therapy, surgery, chemotherapy, and particularly radiation therapy, are further immunosuppressive, which, there is reason to believe, jeopardizes a successful outcome. Immunotherapy seeks to counteract this either by nonspecfic immunoenhancement or by enhancing reactivity to tumor specific antigens. The results of immunotherapy trials in lung cancer patients suggest that survival can be prolonged and survivorship increased by immunotherapy, although the benefit is inconclusuve at present. Optimal conditions for immunotherapy, as presently understood, are outlined. Practical questions about the optimal use of current immunotherapy regimens need to be answered, but a more aggressive approach to lung cancer therapy when combined with immunotherapy seems justified. Im pariicular, the criteria for operability will need to be redefined, particularly as regards oat cell cancer and large tumors which cannot be completely resected but in which "debulking" may contribute to the success of subsequent radiation and immunotherapy. Possible future immunotherapy regimens applicable to lung cancer are proposed, with the reservation that their success is likely to be directly related to their practicability.

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.

Gallium-67 citrate scanning was prospectively evaluated in 55 patients who had lung lesions suspected to be primary carcinoma on chest x-ray films and in whom subsequent histologic diagnosis was obtained. Of 47 patients with histologically proved carcinoma of the lung, 44 (94 per cent) had a positive 67Ga scan. No patient with a positive scan had a benign lesion, so that the positive scan accuracy rate was 100 per cent. All 8 patients with a benign lesion and 3 patients with a malignant lesion had negative scans, for a negative scan accurary rate of 72 per cent for benign lesions. These results give statistical validity for the usefulness of the 67Ga scan in diagnosing carcinoma of the lung (p less than 0.001). Tumor cell type had little effect on the sensitivity of 67Ga scan. The 67Ga scan was equally useful in the evaluation of peripheral and central lesions. There was little difference amount T1, T2, and T3 classified lesions in their ability to take up 67Ga. The 67Ga scan was competitive with mediastinoscopy in assessing mediastinal lymph node metastases and provides a noninvasive method of assessing hilar lymph node metastases. There was a good correlation between the clinical staging of patients with lung cancer based on a chest x-ray film and 67Ga scanning and the staging after surgical treatment based on the histology of the resected specimens.

Because previous studies have suggested that some of the toxic effects of oxygen may result from impaired surfactant phospholipid metabolism, we examined the effects of methylprednisolone on the surfactant system in adult mice exposed to greater than 98% O2. Mice pretreated for 7 days with methylprednisolone, 10 mg/kg/day, had a significantly greater mortality in hyperoxia than saline-pretreated, oxygen-exposed control mice. Their bronchoalveolar lavage fluid contained significantly less desaturated phospholipid, and static pressure-volume curves with air and saline showed decreased lung compliance caused by stiffness of the surface layer. The synthesis of desaturated phospholipids by lung slices in vitro was markedly impaired by the first day of hyperoxia, although in the absence of hyperoxia, it was mildly increased. The increased inhibition of phospholipid synthesis in steroid-treated mice was present even when mice were first given steroids on the day of entry into hyperoxia. These results suggest that methylprednisolone has an unfavorable effect on the surfactant system in oxygen toxicity by accentuating the inhibition of phospholipid synthesis. The possibility that these results could have been due to infection promoted by steroid treatment was considered. No cultural, histologic, or serologic evidence in support of this possibility was found, although infection cannot be conclusively excluded.

Immunotherapy with bacille Calmette-Guérin (BCG) was administered according to a standard regimen to 23 patients with primary lung cancer who had completed conventional treatment, including surgery and/or radiation therapy. Five additional patients did not receive BCG. Skin tests and in vitro lymphocyte studies were performed serially at intervals for 12 months or until death. The aggregate of skin responses to nonmycobacterial antigens and lymphocyte responses to phytohemagglutinin and recall antigens increased only in the group of 7 patients with no clinically evident disease 12 months after the start of BCG administration. The group of 5 patients who did not receive BCG, but who remained clinically disease free, did not experience immunoenhancement, nor did BCG-treated patients with residual or recurrent malignancy. Patients who had received radiation therapy before BCG also did not experience immunoenhancement, but these patients also had recurrent or persistent disease. Enhancement of certain aspects of the immune response to within 1 SD of the response of a group of subjects with nonmalignant pulmonary disease was prognostic of a favorable clinical outcome at 12 months.

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.

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.

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.

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)

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.

Inhaled anticholinergic agents produce as much absolute increase in airflow in chronic bronchitis as in asthma, namely about 0.2-0.3 litres increase in the FEV1 and a doubling of specific airways conductance. Their major advantage in bronchitis is due to the fact that adrenergic agents are relatively poor bronchodilators in this disorder. In bronchitis and emphysema a large number of studies suggest that anticholinergic agents not only are more potent than adrenergic agents but, when given in optimal dosage, achieve all of the available bronchodilatation in these patients. Possible reasons for this are suggested. Quaternary forms, such as ipratropium, have the additional advantage that they are poorly absorbed and thus produce no systemic side effects, giving them a very wide therapeutic margin. This makes them particularly suitable for the older population of which bronchitics are composed, and who are prone to side effects from atropine itself and from other classes of bronchodilators. They can be considered as first line therapy for the relief of symptoms on a day-to-day basis in this group of patients. They may also have a role in the management of acute exacerbations of airways disease, but this has not yet been fully established.

The effect of thyroid hormone on the turnover of mitochondrial DNA and protein was studied in rat heart and liver. Changes in turnover were observed in both thyroidectomized and normal rats following administration of thyroid hormone. In heart and liver the turnover of mitochondrial DNA and protein was slower in thyroidectomized rats than in normal rats. The turnover of mitochondrial DNA and protein was affected similarly following the administration of thyroid hormone, suggesting that mechanisms which control turnover of mitochondrial constituents may be predicated upon a major part of the mitochondrion. In heart a decreased rate of degradation contributes to the increase in total mitochondrial protein. Mitochondrial DNA, labeled before administration of thyroid hormone, turns over, after the start of thyroid hormone administration, at a different rate from that in newly synthesized DNA. The different turnover rates suggest that in liver the pre-existing population of mitochondria is being replaced by another population synthesized under new physiological conditions.

The effect of progressive denaturation of open circular molecules (component II) and supercoiled covalently closed circular molecules (component I) of rat liver mitochondrial DNA has been followed by heating in the presence of formaldehyde and examination in the electron microscope. After heating at 49 degrees C, two, three, or four regions of strand separation were visible in 25% of the component II molecules. Comparisons of the patterns of distribution of these regions in individual molecules indicated that they occurred at at least three specific positions around the molecule. Also, these regions, which were assumed to be rich in adenine and thymine, were within a segment which was less than 50% of the length of the molecule. After heating at 50 degrees C, up to 14 regions of strand separation were observed, but when comparisons were made no clear groupings were found. At 51 degrees C, component II molecules were completely separated into a single-stranded circle and a single-stranded linear piece of similar length. Strand separation was accompanied by shortening of the molecule. At 70 degrees C, single-stranded circles had a mean length of 2.7 micro, compared with 5.0 micro for native molecules. Progressive heating of component I molecules resulted first in conversion to an open circle (I') and then to a second supercoiled form (I''). Visualization of further denaturation products of component I was prevented by crosslinking of the molecule by formaldehyde at high temperatures.