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The influence of chronic administration of ambroxol on the phospholipid-(PL-) content and ultrastructure of lungs has been studied and compared with the effect of chlorphentermine (chlph.). Both drugs are amphiphilic substances. The causative factor of the well-known chlph. induced phospholipidosis-like alterations was suggested to be an inhibition of enzymatic degradation of PL. Rats were intraperitoneally treated five times per week for two weeks with chlph. (0,2 mMol per kg b.w.) and ambroxol (0.2 mMol per kg b.w.), respectively. Lung, heart, liver, kidney and spleen were light microscopically examined, and the lung was studied by electron microscopy. Furthermore, the PL-content of the whole lung tissue, the proportion of phosphatidylcholine (PC), the lung weight/body weight ratio (LM/KM) as well as the dry weight/wet weight ratio (TM/FM) of the lung was calculated. The application of chlph, induced an excessive PL-storage in the lung as indicated by an increase of the PL-content, of the PC-proportion as well as of the LM/KM and TM/FM ratio. The accumulated PL are detectable by electron microscopy, mainly in the lysosomes of macrophages appearing as lamellar or crystalloid inclusions. On the contrary, chronic application of ambroxol does not cause any substantial changes especially no abnormal lysosomal PL-inclusions. Therefore, it is suggested that ambroxol does not interfere with the PL-metabolism in a way comparable to that of the chlph. action.

The influence of the amphiphilic drugs imipramine (150 mg/kg b. w./day) and chloroquine (75 mg/kg b. w./day) on the phospholipid (PL) -metabolism of rat lung, its PL-content and PL-composition were measured in the cell free lung lavage fluid (alveolar surfactant), in the free alveolar cells (mainly alveolar macrophages), and in the residual lung tissue. In addition to the long-term administration (15 applications during a period of 3 weeks), the influence of short-term administration (2 or 4 applications, resp., during a period of 2 or 4 days) was examined. The alveolar macrophages show the largest increase in PL-content. As revealed by its composition the stored PL are of surfactant origin. In chloroquine treated rats the number of macrophages is increased as well. The concentration of stored PL is higher in macrophages of imipramine treated rats. The excessive accumulation of PL in this animal group possibly impairs the clearance function of alveolar macrophages. This is suggested to be the reason for the accumulation of alveolar surfactant in imipramine treated rats. The influence of the drugs on the PL-content of the residual lung tissue was weak. The results of this study show that amphiphilic drugs cause an accumulation of surfactant-PL within the alveolar macrophages and can promote the alveolar surfactant content even after short-term application. The role of alveolar macrophages in alveolar surfactant catabolism is demonstrated.

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.

After one application of paraquat (35 mg/kg body weight) studies of the changes in lung structure in phospholipid content of the alveolar wash as well as in the static pV-curves are performed on adult hooded rats. Pathomorphologically 2, 4, 8, 16, 24 and 48 h after the paraquat intoxication focal atelectases, circumscribed inflammatory infiltrations of the interstitium are predominant as well as an accumulation of macrophages in the interstitium and in the alveolar space. Initially granulocytes dominate in the inflammatory infiltrates; after 8 h lymphoid elements and histiocytes became more and more apparent. 24 an 48 h after the paraquat injection there is a degradation of the alveolar epithelium. After 8-48 h the phospholipid content of the alveolar wash and after 2-48 h the hysteresis loop of the pV-curves are statistically significantly decreased in comparison with control animals. It is assumed, that the paraquat mediated dearrangement of the surfactant system of the lung is caused by an increased degradation in consequence of liberated phospholipases as well as by a decreased or ceased synthesis of the surfactant. The latter may be the consequence of an autooxydative membrane alteration of the endoplasmatic reticulum, the toxic action of the hydrogen peroxide originated by the autooxydation but also of the loss of energy rich substrates.

Alterations of the lung structure, especially of the pneumocytes type II, of asphyxied newborn rabbits were investigated. Experiments were carried out on pregnant does shocked by thrombin- and Pamba-applications on the 28th, 29th and 30th day of gestation and on their newborns delivered by caesarian section at these days and killed after one or five hours life-time. Histologically, adult rabbits show characteristic alterations in an early phase of the shock. Lung alterations are the main findings in the newborns. Atelectases and, additionally, disturbances of circulation, permeability and also hyaline thrombi are seen. Lamellar bodies within the pneumocytes type II show a significant decrease of the lamellae and the whole osmiophilic material. The alterations of immature newborns are more severe than those of mature animals and also more severe after the longer life-time. These alterations are considered as a result of decreased synthesis of surface active phospholipids.

Alterations of the lung- and lung lavage fluid-phospholipids (PL's) after a maternal thrombin-shock have been studied in 1 and 5 h old newborn rabbits delivered at days 28 and 30 of gestation. In lung wash the amount of PL increases during the period of gestation and during the first hours of life. In asphyxiated mature animals the PL-content is statistically significantly decreased. The very low PL-content of the lung wash in premature born animals is not affected by asphyxia. The amount of phosphatidyl choline (PC) as a percentage of total PL is unchanged in all animals studied. The PL and PC content in the lung tissue follows the same developmental pattern but the differences are not statistically significant. Changes in the lung weight/body weight (LW/BW)--ratio after asphyxia show a disturbed development of the newborn lung, too.

In continuation of previous experiments in adult rats the alteration in content and composition of lung phospholipids (PL) and lung structure of newborn rats of different gestational age was studied after three administrations of the amphiphilic drugs imipramine (75 mg/kg b.w.) and chloroquine (50 mg/kg b.w.). The fetuses were obtained by Cesarean section on day 20, 21, or 22 of gestation. Morphological examinations of the lungs of drug treated 21-day-old fetuses revealed a substantially better aeration than nontreated controls. 20 and 22 days old fetuses showed no differences in aeration between drug and saline treated rats. Analogous results were obtained with respect to the 1 h survival rate of newborns. Furthermore, imipramine and chloroquine cause a premature development of the pneumocytes type II as shown by electron microscopy. An increased PL content as well as disaturated phosphatidylcholine (DSPC) and phosphatidylglycerol (PG) proportion of fetal lungs, especially in animals born on day 21 of gestation, were found after drug treatment. The results suggest an acceleration of maturation of the pneumocytes type II in fetal lungs induced by amphiphilic drugs.