Exposure to crystalline silica or treatment with chlorphentermine increases vitamin E levels in rat alveolar lavage materials.

Previous studies have shown that vitamin E may be an integral part of lung surfactant and may function to protect this material from oxidant damage. Therefore, we measured the vitamin E levels in alveolar lavage materials from rats exposed to crystalline silica or treated with chlorphentermine (CP), two treatments that are known to increase surfactant phospholipids (PL) by different mechanisms. Silica exposure leads to increased PL synthesis, and CP treatment causes a reduction in PL degradation. Two different silica preparations, HCL-washed and unwashed silica, were used because exposure to each of them leads to different degrees of phospholipidosis. Exposure to HCL-washed silica results in a more than 17-fold increase in lavage PL and protein levels and a 12.2-fold increase in the amount of vitamin E. Exposure to unwashed silica leads to an approximately 7-fold increase in PL and proteins and a 5.8-fold increase in lavage vitamin E. Following treatment of rats with CP, there is a 15- to 19-fold increase in lavage PL and proteins and a 13.6-fold increase in vitamin E. When the results are expressed as micrograms vitamin E per milligram of lavage PL or protein, there is not much difference between controls and each treatment group. Because surfactant synthesis occurs in the endoplasmic reticulum, we also measured vitamin E in lung microsomes. Both silica exposure and CP treatment also lead to 1.8- to 2.5-fold increases, respectively, in the lung microsomal levels of vitamin E. These results demonstrate that alveolar lavage vitamin E levels are elevated along with lavage PL and proteins, and lung microsomal vitamin E levels are increased following exposure of rats to silica or treatment of the animals with CP.

Role of phospholipase C in chlorphentermine-induced pulmonary phospholipidosis in rat.

Daily, oral administration of chlorphentermine (60 mg/kg) for 5 days to rats produced a significant increase in the concentration of whole lung total phospholipid as well as sphingomyelin, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. Similarly, a significant elevation in total and all individual phospholipid components was found in the lysosomal fraction of chlorphentermine-treated rat lung. In contrast, the activities of pulmonary Na+,K+-ATPase and alkaline phosphatase, enzymatic markers of membrane function, were not markedly affected by chlorphentermine treatment. The observed lung phospholipidosis was accompanied by inhibition of phospholipase C activity. Regardless of the phospholipid substrate, chlorphentermine significantly decreased pulmonary phospholipase C to approximately the same extent. Our data show that accumulation of phospholipid in whole lung and lysosomes is associated with an inhibition of phospholipase C activity.

Chlorphentermine-induced alterations in the lungs of vitamin E-deficient and -supplemented rats: quantitative ultrastructural analysis of Type II Cell response.

Response of alveolar Type II (T-II) cells of male Sprague-Dawley weanling rats maintained on vitamin E (VE)-deficient and -supplemented diets to chlorphentermine (CP) treatment was evaluated. Ultrastructural and quantitative procedures were used to assess the T-II cell-drug interaction. Subjective examination of photomicrographs revealed numerous disrupted surfactant lamellar bodies in the CP-treated animals, as compared to fewer in controls. In addition, an unusual amorphous material was associated with these cells in drug-treated animals. Quantitative assessment confirmed the above subjective impression and revealed an increase in the size of T-II cells in treated rats. Morphometric evaluation showed that CP treatment significantly altered the volume density of cytoplasm, mitochondria, and rough endoplasmic reticulum (RER). Furthermore, a significant interaction between the diet and treatment with respect to volume fractions of mitochondria, RER, and Golgi complex was observed. The present study indicates that cytoplasmic components in T-II cells are altered as a result of CP treatment and that VE status of the animals influences the nature and extent of these alterations.

Alcohol-induced bronchospasm in an asthmatic patient: pharmacologic evaluation of the mechanism.

A 23-year-old Asian with histamine-reactive asthma complained of recurrent chest tightness, nasal congestion and flushing immediately after drinking minimal amounts of alcoholic beverages. He was extensively studied to determine the possible mechanism of his alcohol-induced respiratory symptoms. Drinking of either beer or 95 percent ethanol in apple juice immediately provoked vasomotor signs and moderately severe bronchospasm (54 percent and 73 percent decreases in specific airway conductance, respectively), which spontaneously improved over 30 minutes and two hours, respectively. Intravenous and inhaled ethanol caused less bronchospasm than observed with oral ethanol, and recovery was rapid. Pretreatment with cromolyn sodium (inhaled or oral) and isoproterenol had no inhibitory effect on the alcohol-induced bronchoconstriction, whereas atropine, acetylsalicylic acid, cyproheptadine, and chlorpheniramine appeared to have a partial inhibitory effect. Approximately 70 percent inhibition was observed after chlorpheniramine. Observations in this patient suggest that the bronchoconstriction induced by alcoholic beverages is related to their ethanol content and may be related to formation or release of one or more bronchoconstrictor and vasoactive compounds, including a stimulant of histamine1-receptors. The route of ethanol administration may also influence the bronchospastic response.

Morphological and biochemical alterations of the lung after application of chlorphentermine.

The influence of short-term and chronic administration of chlorphentermine (Chlph) on the structure and phospholipid (PL)-content of the lungs was studied in guinea pigs. The drug was given daily in a dose of 40 mg per kg body weight i.p. The PL-content of the whole lung as well as the phosphatidyl choline (PC)-portion were estimated in animals treated with Chlph for 4, 5 and 6 weeks. In a further experiment, the influence of 2, 4 and 28 days application on the PL-content of the lung lavage fluid separated into the acellular and cellular (macrophage) fraction was examined. Morphologic studies of lung, liver, heart, kidney, spleen, brain, and pancreas supplemented the PL-content analysis. The amount of PL in the whole lung increases continuously with the duration of the treatment but only moderately. The PC-fraction of the total PL remains constant throughout the experiment. A substantially greater increase was detected in the lung lavage fluid whereby the cellular fraction is most affected. Very important is the result that the PL-content of the lung lavage fluid reaches its highest level already after two Chlph-injections. After short-term administration the morphological examination of the lung mainly shows inflammatory infiltrations, whereas after long-term application a foam cell reaction is mainly localized in the interstitium. The studies show that an increase of the amount of lung sufactant in guinea pigs is possible following Chlph administration.

Effects of prolonged administration of chlorphentermine on the rat lung.

Prolonged administration of the anorexigen chlorphentermine hydrochloride to young male Wistar albino rats for up to one year failed to induce in them either right ventricular hypertrophy or hypertensive pulmonary vascular disease. There was, however, the development of a pronounced pulmonary histiocytosis. Studies by light and electron microscopy showed that these histiocytes disintegrated to liberate their lamellar inclusions into the alveolar spaces, producing a picture reminiscent of alveolar proteinosis. Fibrosing alveolitis occurred in only one animal and was thought to be related to inflammatory changes rather than as a development of the pulmonary histiocytosis. Attention is drawn to the fact that thick-walled large pulmonary arteries are entirely normal in rats and should not be misinterpreted as evidence of hypertensive pulmonary vascular disease in test animals.