Kupffer cell-derived 95kDa type IV collagenase/gelatinase Characterisation, regulation and role in liver disease

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Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis

Liver fibrosis results from a relative imbalance between synthesis and degradation of matrix proteins. We have previously described release of the potent collagen-use inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP- 1), by culture-activated human hepatic stellate cells (HSCs). In this study, we have investigated the relative expression of TIMP-1 and interstitial collagenase in culture-activated rat HSCs and rat models of liver injury and fibrosis. The complementary DNA (cDNA) for rat TIMP-1 was obtained by homology polymerase chain reaction (PCR) and sequenced. By Northern analysis using this probe, TIMP-1 messenger RNA (mRNA) expression was up-regulated with HSC activation by culture on plastic as defined by cellular expression of procollagen-1. Interstitial collagenase mRNA was expressed in early culture (<4 days) but became undetectable in more activated cells (7-21 days). By activity assay of serum-free cell-conditioned media, TIMP-1 was found to be released in increasing concentrations with duration of culture on plastic. Expression of TIMP-1, interstitial collagenase, and procollagen-1 mRNAs were studied in rat models of biliary and parenchymal injury (bile duct ligation and CCl4 administration) by ribonuclease protection assay. TIMP-1 mRNA expression was increased at 6, 24 hours, and 3 days after bile duct ligation and was also shown to rise in acute CCl4 liver injury and remain elevated as the liver became fibrotic. TIMP-1 expression preceded procollagen-1 expression in both models. In contrast, interstitial collagenase mRNA levels remained similar to control values throughout both models of liver injury. Total cellular RNA from hepatocytes, HSCs, and Kupffer cells freshly isolated from livers after acute CCl4 injury was subjected to Northern analysis. TIMP-1 transcripts were observed in nonparenchymal cells only. We suggest that increased expression of TIMP-1 relative to interstitial collagenase by HSCs may promote progression of liver fibrosis in these rat models by preventing degradation of secreted collagens.Articl

Work-related fatigue and recovery: the contribution of age, domestic responsibilities and shiftwork

Aim: This paper reports a study of the relationship between age, domestic responsibilities (being partnered and having dependents), recovery from shiftwork-related fatigue and the evolution of maladaptive health outcomes among full-time working female nurses. Background: Several studies have suggested that full-time working women with family responsibilities are at greater risk of developing work-related fatigue problems than single women without these responsibilities. Method: A questionnaire was distributed in 2004 to 2400 nurses at two hospitals in Australia, and 1280 responses were obtained (response rate 54%). The data from a purposive sample of 846 full-time working nurses are reported here. Findings: Domestic responsibilities were not related to differences in fatigue and recovery. Our results suggested that for full-time shiftworking nurses, being part of a family structure, may actually be protective against the development of maladaptive fatigue. The most important factor determining maladaptive fatigue outcome was shift pattern worked, particularly rotation including night duty. The effect of age was equivocal. The youngest age group reported the highest fatigue and poorest recovery compared to the oldest group, who reported the best characteristics. However, this latter group may represent a particularly well-adapted ‘survivor cohort’. The relationship between age and fatigue was partly confounded by older, experienced, nurses with greater job responsibilities, working fewer multiple shifts including night duty. In general, increasing age was not associated with poorer recovery or higher maladaptive fatigue. Conclusions: Unpredictable internal shift rotations, including night duty, which are traditional and typical in nursing, are inimical to maintaining nurses’ health. More creative approaches to rostering for nurses working multiple shifts are a necessary step towards reducing wastage from the profession due to chronic work-related fatigue. Younger nurses in particular, may need more support than is currently recognized if they are to be retained within the profession