Dihydroartemisinin-Stimulated Hyperplasia of Rat Lung Smooth Muscles

Problem statement: Dihydroartemisinin was shown to produce two types of inhibitory effects on the cardiac muscles of rats. It was also shown to stimulate haemopoiesis in the lungs, live r, spleen, intestine and kidney of rats. This study at tempted to find out the nature of the effect of ora l dihydroartemisinin on the lungs of Wistar albino ra ts. Approach: The effects of dihydroartemisinin on the tissues of the lungs of wistar albino rats were inv stigated with five doses of Dihydroartemisinin (DHA) administered for 5 days by oral intubation. T he five tested doses were 1 mg kg , a repeated dose of 1, 2, 60 and 80 mg kg −1 DHA. Results: Histopathological examination of the tissue micrographs of the lungs of the dihydroartemisinin treated rats showed that in comparism with those of the controls, DHA had no adverse effects on the tis sue of the lungs of the rats but rather produced a direct stimulatory effect on the smooth muscles of the lungs. This stimulation caused hyperplasia of these tissues which was observable histologically i n tissue micrographs of the lungs. These effects of dihydroartemisinin on the tissues of the lungs of W istar albino rats were dose, repetition and time dependent. Conclusion: These growth hormone-like stimulatory effects of d ihy roartemisinin on the smooth muscles of the lungs suggest that DHA enhanc ed the functioning capacity of the lungs of the DHA-treated rats. These results suggest that dihydr oartemisinin has possible respiration enhancement effects.


INTRODUCTION
Dihydroartemisinin is acclaimed for its rapid clearance of malarial parasites in uncomplicated and complicated malaria. Little attention was paid to the organ effects of DHA in the past. However some recent studies reported the direct effects of dihydroartemisinin on the smooth muscles of the intestine of rats ; on the smooth muscles of the bronchial tubes; (Uchechukwu et al., 2011).
This study investigated the effects of oral dosage regimens of DHA on the lungs of Wistar albino rats.

MATERIALS AND METHODS
The test and control rats were weighed 10 min before the administration of the first dose and 10 min after the administration of the last dose of each of the five doses of DHA tested. Equivalent doses of distilled water to the administered doses of DHA were administered to the control rats in each experiment.
The tested doses of DHA were 1 and 1 mg Kg −1 which was repeated after an interval of 1 week, 2, 60 and 80 mg Kg −1 . Young adult rats weighing 75-90 Kg were given the repeated 1 mg Kg −1 dose while adult rats weighing 104-106 gr were given the remaining 4 doses of DHA tested. Five test and four control rats were used for each experiment. Each dose of DHA or distilled water was administered by oral intubation for 5 days. The rats given the repeated 1 mg Kg −1 dose received the treatment for 5 days, rested for 1 week and received the 5-day treatment again.
The test and control rats were sacrificed 24 h after the administration of the last dose in each experiment. Their lungs were then harvested and their tissue photomicrographs prepared through conventional methods.

RESULTS
The weight gain in the DHA-treated rats was greater than those of the control rats. It was dose dependent. The 2 mg kg −1 DHA-treated rats had the greater weight gain. Gross anatomical examination and comparism of DHA-treated and control rats showed that that DHA treatment had no adverse effects on the lungs of the test rats. Histopathological examination and comparism of the lung tissue of the DHA-treated and control rats showed that DHA treatment with the 5 dosage levels of DHA tested had no adverse effects on the tissues of the lungs of the treated rats. On the other hand, DHA treatment produced a direct dose, repetition and time dependent stimulation of the growth and proliferation of the smooth muscles of the lungs (Fig. 1). The 2 mg kg −1 DHA dose was the maximal response dose.

DISCUSSION
The direct stimulation of growth and proliferation of the smooth muscles of the lungs by dihydroartemisinin suggests that DHA strengthened the structural and functional status of the lungs. The dose and repetition dependent weight gain in the DHA treated rats which followed the same pattern as the proliferation of the lung smooth muscles supports our observations on the cell multiplication effects of DHA on the lung smooth muscles of the lungs.
The findings of this study suggest that dihydroartemisinin has direct growth hormone-like stimulatory effects on rat lung smooth muscles.
This has beneficial implications for the respiratory functional capacity of the malaria patient who is on DHA (artemisinin) treatment.

CONCLUSION
The direct stimulant effects of dihydroartemisinin on the lung smooth muscles suggest that DHA might be of use in the treatment or prevention of lung cancer. Transferrin was found to overcome drug resistance to artemisinin in human small-cell lung carcinoma cells (Sadava et al., 2002) which shows the importance of the interactions of artemisinin with hemin of haemoglobin or myoglobin in its anticancer effects. Moreover our studies had recommended the suitability of dihydroartemisinin fo prevention of cancer or the treatment of early (trace) stage of cancer (Nedosa et al., 2011b).