SummaryPlasmodium berghei is the causative agent of rodent malaria and is widely used as a model system to study the liver stage of Plasmodium parasites. The entry of P. berghei sporozoites into hepatocytes has extensively been studied, but little is known about parasite-host interaction during later developmental stages of the intracellular parasite. Growth of the parasite far beyond the normal size of the host cell is an important stress factor for the infected cell. Cell stress is known to trigger programmed cell death (apoptosis) and we examined several apoptotic markers in P. berghei -infected cells and compared their level of expression and their distribution to that of non-infected cells. As none of the apoptotic markers investigated were found altered in infected cells, we hypothesized that parasite infection might confer resistance to apoptosis of the host cell. Treatment with peroxide or serum deprivation induced apoptosis in non-infected HepG2 cells, whereas P. bergheiinfected cells appeared protected, indicating that the parasite interferes indeed with the apoptotic machinery of the host cell. To prove the physiological relevance of these results, mice were infected with high numbers of P. berghei sporozoites and treated with tumour necrosis factor (TNF)-α α α α / D -galactosamine to induce massive liver apoptosis. Liver sections of these mice, stained for degraded DNA, confirmed that infected cells containing viable parasites were protected from programmed cell death. However, in nontreated control mice as well as in TNF-α α α α -treated mice a small proportion of dead intracellular parasites with degraded DNA were detected. Most hepatocytes containing dead parasites provoked an infiltration of immunocompetent cells, indicating that these cells are no longer protected from cell death.

Background/Aims: Severe lung injury, responsible for up to 15% of mortality in acute necrotizing pancreatitis patients, is promoted by neutrophil (PMN) migration into the lung. We have previously demonstrated that pulmonary injury in acute pancreatitis is mediated by PMN-derived matrix metalloproteinase-9 (MMP-9). This study was conducted to evaluate the ability of the broad-spectrum MMP inhibitor doxycycline to prevent secondary pulmonary injury in acute pancreatitis. Methods: Eighteen rats were randomized into three groups: severe pancreatitis (SAP), severe pancreatitis + doxycycline (SAP+Dox) (30 mg/kg body mass) or control. Acute pancreatitis was induced by intraductal glycodesoxycholic acid and i.v. stimulation with cerulein. Lung sections were histologically graded for edema, microthrombi, atelectasis and hemorrhage. Active MMP-9 in lung tissue was measured with fluorescent assay (ELISA). Naphtol-AS-D-chloroacetate esterase staining was used to determine pulmonary PMN infiltration. The inhibitory effect of doxycycline on MMP-9-induced transmigration was confirmed in a Matrigel transmigration assay. Results: Addition of doxycycline significantly reduced TNF-α-induced PMN transmigration across Matrigel membrane (12.6 ± 2.6 vs. 20.1 ± 3.9 PMNs; p < 0.05). SAP+Dox showed decreased concentration of active MMP-9 in lung tissue (37.89 ± 1.75 vs. 46.29 ± 3.68 ng/ml; p < 0.05) and as a result decreased pulmonary infiltration of PMNs (21.2 ± 5.1 vs. 32.5 ± 6.8; p < 0.05). Histological evaluation revealed decreased pulmonary edema (1.83 ± 0.41 vs. 2.33 ± 0.51, p < 0.05), atelectasis (1.67 ± 0.52 vs. 2.33 ± 0.52; p < 0.05) and pulmonary hemorrhage (2.5 ± 0.55 vs. 1.83 ± 0.41; p < 0.05) in SAP+Dox vs. SAP. These findings were paralleled by reduced pulmonary expression of active MMP-9. Conclusions: Inhibition of MMP-9 activity with doxycycline reduced pancreatitis-associated lung injury and expression of MMP-9 in pulmonary tissue. Doxycycline reduced PMN migration in vitro and in vivo and therefore might represent a novel strategy for the prevention of secondary pulmonary complications in acute pancreatitis.

In a routine study of vaginal smears of postmenopausal women we had previously established the connection between a somatic or psychological stress on the one hand, and an increase in the number of superficial cells in the vaginal smears on the other. This phenomenon was further analyzed by a study of the vaginal smears of rats of the Wistar strain. Artificial stress was induced by swimming tests. Only a total stress proved adequate for our experiments. Stress produced an increase in the number of cornified cells in the vaginal smears of oophorectomized rats. This phenomenon failed to appear when the animals were subsequently adrenalectomized. In most instances hypophysectomy did not prevent this increase of cornified cells after stress. Bilateral removal of the adrenal medulla in oophorectomized animals reduced the number of animals which reacted positively to the stress. The effect was totally abolished when the animals were pretreated with phentolamine (Regitine) which completely blocks the sympathetic tissue. In spayed rats ACTH induced the appearance of cornified cells, but not after adrenalectomy or hypophysectomy. Adrenaline administration only rarely evoked a response. The vaginal smears were not influenced by the administration of testosterone, progesterone, cortisol, aldosterone or spirolactone. Oestrogens in a physiological dose brought about a prompt response. The results indicate that stress induces a release of oestrogens or oestrogenic substances from the adrenal cortex. The most important pathway seems to follow the sympathetic nervous system. As a hypothesis the pathway is suggested to proceed from the hypothalamus via the sympathetic tissue to the adrenal.

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