The role of cathepsin K in lung development and newborn chronic lung injury.

Chronic lung diseases, specifically bronchopulmonary dysplasia (BPD), are still causing mortality and morbidity amongst newborn infants. High protease activity has been suggested to have a deleterious role in oxygen-induced lung injuries. Cathepsin K (CatK) is a potent protease found in fetal lungs, degrading collagen and elastin. We hypothesized that CatK may be an important modulator of chronic lung injury in newborn infants and neonatal mice. First we measured CatK protein levels in repeated tracheal aspirate fluid samples from 13 intubated preterm infants during the first two weeks of life. The amount of CatK at 9-13 days was low in infants developing chronic lung disease. Consequently, we studied CatK mRNA expression in oxygen-exposed wild-type (WT) rats at postnatal day (PN) 14 and found decreased pulmonary mRNA expression of CatK in whole lung samples. Thereafter we demonstrated that CatK deficiency modifies lung development by accelerating the thinning of alveolar walls in newborn mice. In hyperoxia-exposed newborn mice CatK deficiency resulted in increased number of pulmonary foam cells, macrophages and amount of reduced glutathione in lung homogenates indicating intensified pulmonary oxidative stress and worse pulmonary outcome due to CatK deficiency. Conversely, transgenic overexpression of CatK caused slight enlargement of distal airspaces with increased alveolar chord length in room air in neonatal mice. While hyperoxic exposure inhibited alveolarization and resulted in enlarged airspaces in wild-type mice, these changes were significantly milder in CatK overexpressing mice at PN7. Finally, we showed that the expression of macrophage scavenger receptor 2 (MSR2) mRNA was down-regulated in oxygen-exposed CatK-deficient mice analyzed by microarray analysis. Our results demonstrate that CatK seems to participate in normal lung development and its expression is altered during pulmonary injury. In the presence of pulmonary risk factors, like high oxygen exposure, low amount of CatK may contribute to aggravated lung injury while sustained or slightly elevated amount of CatK may even protect the newborn lungs from excessive injury. Besides collagen degrading and antifibrotic function of CatK in the lungs, it is obvious that CatK may affect macrophage activity and modify oxidative stress response. In conclusion, pulmonary proteases, specifically CatK, have distinct roles in lung homeostasis and injury development, and although suggested, broad range inhibition of proteases may not be beneficial in newborn lung injury.

Fiktiivisen kirjallisuuden maailmasta monikulttuuriseen Suomeen. Ennakointikertomus kirjallisuudenopetuksen ja monikulttuurisuuskasvatuksen välineenä

From the world of fiction literature into multi-cultural Finland. Anticipatory story as an educational tool in teaching of literature and multiculturalism The research clarifies the relationship between reading fiction literature and multicultural value education in basic education. The research focuses on the subject didactics of mother tongue and literature and on the literature teaching in particular. The objective is to develop a method that is easily transferable into a teaching context so as to intensify the educational discussion based on fiction literature. In essence, understanding fiction literature and the ethical and moral thinking resemble one another, because both of them aim at empathizing with the thinking of a person or with a situation foreign to oneself. For this reason fiction literature is ideally suited for the discussion on ethical and moral values within a subject entity in the basic education. The empirical unit of the research consists of two parts. The first part explains how youth novels published in the years 1993 – 2007 describe multiculturalism in Finnish society. Books on multiculturalism are still few in number within youth literature, and people with a foreign background are mainly minor or background characters in such literary works. Nevertheless, youth novels serve well as a starting point for an educational discussion about multicultural issues. More often than not characters in youth novels are stereotypes and even opposite to each other. The juxtaposing makes a young reader question the stereotypes associated with immigrants. Besides the stereotype, reference to a prototype or a model is possible. The second part tests the usefulness of an anticipatory story based on a fictive text for an educational discussion about multicultural issues. The empirical material was collected from the eighth-grade teaching groups in basic education as follows: one teaching group was an immigrant group, the second one a group of Finns with experience of immigrants while the third group of students had hardly any experience of immigrants. The anticipatory stories were written on the basis of extracts from youth novels with multicultural themes. The material collected for a total of 120 anticipatory stories was analysed by using meaning cue analysis. Using the meaning cue analysis, the anticipatory stories were divided into three groups: stories with predominantly positive meaning cues of interculturalism, ambivalent stories with both positive and negative meaning cues of interculturalism and the stories with predominantly negative meaning cues of interculturalism. The meaning cues produced by girls and boys differ from one another, in particular, by the negative meaning cues of interculturalism. For girls, the predominant meaning cue is fear whereas for boys, it is that of violence. It would also seem that the students, in particular, boys with little experience of immigrants produce more negative meaning cues of interculturalism than do immigrants or Finnish students with experience of immigrants. Further still, it seems that active reading of fiction literature affects the meaning cues of interculturalism in an ambivalent direction. In the way of youth novels this is understandable, because youth novels in general are made up of opposite characters and meaning cues. The less the student takes an interest in reading, the more he used meaning cues from outside the parent text for his anticipatory story. No doubt it would be possible to use fiction literature in the literature education to a much higher extent than it is being used today whereby the literature could be used in basic education for reviewing subject entities or study contents of other study subjects. By way of an anticipatory story and the meaning cue analysis, it is possible to intensify the educational discussions based on fiction literature. However, using fiction literature in the literature education requires consideration of the specific genre of fiction literature.

Superoxide dismutase 3-mediated cell survival and proliferation

This dissertation studies the signaling events mediated by the extracellular superoxide dismutase (SOD3). SOD3 is an antioxidant enzyme which converts the harmful superoxide into hydrogen peroxide. Overproduction of these reactive oxygen species (ROS) in the cellular environment as a result of tissue injury or impaired antioxidant defense system has detrimental effects on tissue integrity and function. However, especially hydrogen peroxide is also an important signaling agent. Ischemic injury in muscle causes acute oxidative stress and inflammation. We investigated the ability of SOD3 to attenuate ischemia induced inflammation and to promote recovery of skeletal muscle tissue. We found that SOD3 can downregulate the expression of several inflammatory cytokines and cell adhesion molecules thus preventing the accumulation of oxidant-producing inflammatory cells. Secondly, SOD3 was able to promote long-term activation of the mitogenic Erk pathway, but increased only briefly the activity of pro-survival Akt pathway at an early stage of ischemic inflammation, thus reducing apoptosis. SOD3 is a prominent antioxidant in the thyroid gland where oxidative stress is constantly present. We investigated the role of SOD3 in normal thyroid follicular cells and the changes in its expression in various hyperproliferative disorders. We first showed that SOD3 is TSH-responsive which indicated its participation in thyroid function. Its principal function seems to be in follicular cell proliferation since knockdown cells were deficient in proliferation. Additionally, it was overexpressed in goiter tissue. However, SOD3 was consistently downregulated in thyroid cancer cell lines and tissues. In conclusion, SOD3 is involved in tissue maintenance, cell proliferation and inflammatory cell migration. Its mechanisms of action are the activation of known proliferation/survival pathways, inhibition of apoptosis and regulation of adhesion molecule expression.