bluuebunny/crossref_metadata_2025 huggingface dataset:
Constipation in cancer patients: Prevalence, pathogenesis, and cost‐related issues
Authors: Fallon Marie T.
Published: March 2004

Among patients with advanced cancer, troublesome and persistent constipation is a more common symptom than pain. The major causes of constipation in cancer patients are inactivity, treatment with opioids, and poor fluid intake and nutrition. Opioids act to both decrease gut motility, decrease intestinal secretion and therefore harden the stool. Additional aetiologies of constipation may be related to the cancer itself, general debility, concomitant diseases, or medication use. Analysis of results from one centre participating in a multicentre, prospective, longitudinal follow‐up study, has confirmed the high incidenceof constipation among opioid‐treated cancer patients and revealed that even optimal management of this symptom is only modestly successful in reducing constipation. This study also indicated that, in constipated cancer patients, bowel care entailed an average of 20 to 70 min per week of medical time and 55 to 120 min per week of nursing time, underscoring the high financial cost of this symptom to the health care system. Accordind to another study, which involved 50 consecutive cancer patients referred to a palliative care unit, the development of resistant constipation was independent of morphine dose. However, this study revealed a highly statistically significant correlation between resistant constipation and patient functional status, which highlights the critical and often underestimated role of immobility in the development of constipation.
The constipation‐inducing potential of morphine and transdermal fentanyl
Authors: Haazen Ludo , Noorduin Henk , Megens Anton , Meert Theo
Published: March 2004

Constipation is an almost universal side‐effect associated with chronic opioid analgesia. The resulting discomfort can for some patients be more severe than the pain itself, leading to a reduction of analgesic use and consequently to increased pain. Clinical trials consistently show less constipation in patients treated with transdermal fentanyl than in patients receiving oral morphine. Several reasons can be identified for this finding: owing to its higher lipophilicity, fentanyl penetrates the blood‐brain barrier more easily and lower dosing is possible; owing to the transdermal route of administration of fentanyl, comparatively less opioid is available in the gastrointestinal tract to block local opioid receptors; finally, the transdermal route of administration leads to stable plasma levels of fentanyl over 72 h and hence minimises the probability of overdosing that can occur with multiple daily dosing. Further research is needed to establish whether these effects can also be extrapolated to other peripheral effects of opioids such as nausea and vomiting.
Constipation, patients and lifestyles
Authors: Ling Julie
Published: March 2004

Constipation is an issue which nurses in palliative care deal with on a day‐to‐day basis. As with many problems in this specialty, constipation is multifactorial in nature and therefore it can be a complex problem to treat. It is known to be caused or exacerbated by the use of opiods and therefore should be anticipated and treated prophylactically. Good assessment is important and a thorough history of the patient's bowel habits and patterns should be obtained. Management of constipation should incorporate both pharmacological and non‐pharmacological approaches. Education plays an important role in both the prevention and treatment of constipation. In conclusion, the nursing care of patients with constipation is aimed at providing a realistic and acceptable bowel pattern for each patient as an individual according to patient need, general condition and lifestyle.
High intake of added sugar among Norwegian children and adolescents
Authors: Øverby Nina C , Lillegaard Inger TL , Johansson Lars , Andersen Lene F
Published: March 2004

Objective:

It is debated whether the intake of added sugar displaces micronutrient-rich foods and dilutes the nutrient density of the diet, and whether there is a link between sugar and the increased rate of obesity. The objectives of this study were to examine the effect of added sugar on the intakes of energy, micronutrients, fruit and vegetables, and to examine the association between intake of added sugar and age, sex, body mass index, physical activity, inactivity and parents' education.

Design:

Participants recorded their food intake in pre-coded food diaries for 4 days and filled in a questionnaire about physical activity, watching television (TV)/using a personal computer (PC) and parents' education.

Subjects:

Three hundred and ninety-one 4-year-olds, 810 students in the 4th grade (9 years old) and 1005 in the 8th grade (13 years old) were included in the study.

Results:

The intakes of all nutrients, except α-tocopherol among 4-year-olds and vitamin C among 4-year-olds and 4th graders, decreased with increasing content of added sugar in the diet. Moreover, high consumers of added sugar had a 30–40% lower intake of fruit and vegetables than did low consumers. A negative association was observed between consumption of added sugar and body mass index among girls in the 8th grade (P= 0.013), whereas a positive association was observed among 4-year-old boys (P= 0.055). Associations between physical activity, hours spent watching TV/using a PC, parents' education and the energy intake from added sugar varied in the different age groups.

Conclusions:

This study showed a negative association between the intake of added sugar and intakes of micronutrients, fruit and vegetables. The negative association between sugar intake and intake of fruit and vegetables is important from a public health perspective, since one of the main health messages today is to increase current intake of fruit and vegetables.
Eating habits, beliefs, attitudes and knowledge among health professionals regarding the links between obesity, nutrition and health
Authors: Hankey CR , Eley S , Leslie WS , Hunter CM , Lean MEJ
Published: March 2004

Objective:

To document knowledge, attitudes, beliefs and eating habits of health professionals with respect to obesity, nutrition and weight management.

Design:

A self-complete questionnaire postal survey.

Setting:

Primary care and dietetic practice in Scotland.

Subjects:

A systematic stratified sample of 2290 subjects incorporated general practitioners (n = 1400), practice nurses (n = 613) and all practising dietitians (n = 360) who were members of the British Dietetic Association.

Results:

The overall response rate was 65%. All professionals showed a clear understanding of nutrition and health. Understanding of obesity as a disease and of the effectiveness of weight management using low-energy diets was limited. Below 10% had carried out audit to determine the incidence of obesity and overweight, and most were uncertain about their own effectiveness in delivering weight management advice.

Conclusion:

This study confirms that health professionals have some knowledge of nutrition and weight management but are unclear how to deliver effective weight management advice. Further training is justified to ensure the effective provision of nutritional advice to patients.
Reliability of parental and self–reported determinants of fruit and vegetable intake among 6th graders
Authors: Bere Elling , Klepp Knut-Inge
Published: March 2004

Objective:

To assess the reliability of newly developed questionnaires measuring theoretical constructs believed to predict fruit and vegetable consumption among 6th–grade pupils.

Design:

Participating pupils and parents completed questionnaires twice, 14 days apart.

Setting:

One hundred and twenty–nine pupils from 6th–grade classes (average age: 11.9 years) at two schools in Norway and their parents were invited to participate.

Results:

The test–retest reliability was found to be good or very good for scales reported both by the pupils and their parents. All scales showed acceptable to strong correlations between time 1 and time 2, and only one scale had significant different mean values at the two times. The internal consistency reliability of the scales was acceptable to good.

Conclusions:

Sixth graders and their parents are able to provide reliable reports on theoretical determinants of the pupilapos;s fruit and vegetable consumption.
Vitamin D status of middle-aged women at 65–71°N in relation to dietary intake and exposure to ultraviolet radiation
Authors: Brustad M , Alsaker E , Engelsen O , Aksnes L , Lund E
Published: March 2004

Objective:

To determine the vitamin D status of middle-aged women living in the Norwegian arctic and its relationship with vitamin D intake and exposure to ultraviolet (UV) radiation.

Design:

Cross-sectional study.

Subjects and setting:

This study is based on measurements of 25-hydroxyvitamin D (25(OH)D) levels in a sub-sample of the Norwegian component of the EPIC biological bank, which consists of blood samples from a random selection of participants in the Norwegian Women and Cancer Study. From November 2001 until June 2002, 309 blood samples were collected from a total of 443 invited middle-aged women (44–59 years) in northern Norway (65–71°N) (crude response rate, 69.8%). Questionnaire data provided information on dietary sources of vitamin D and UV exposure.

Results:

Median plasma 25(OH)D concentration for the whole group was 55.0 nmol l−1 (range 8.1–142.8 nmol l−1). Vitamin D intake was a significant predictor of 25(OH)D status (P = 0.0003). The time of the year when the blood sample was collected significantly predicted plasma 25(OH)D level (P = 0.005). Levels of 25(OH)D were positively associated (P = 0.0002) with estimated hours per day of exposure to UV-B radiation. Residing in northern Norway during the summer prior to blood sampling was negatively associated with 25(OH)D concentration (P = 0.001). The prevalence of moderate hypovitaminosis D was highest in January–February, when a quarter of the participants had 25(OH)D concentrations ≤37.5 nmol l−1.

Conclusions:

Increased ingestion of marine food items that provide vitamin D should be promoted and further studies should be carried out to investigate vitamin D status in arctic populations in relation to both UV exposure and traditional food sources.
Role ambiguity, role conflict and job satisfaction among physical education teachers in Greece
Authors: Koustelios Athanasios , Theodorakis Nicholas , Goulimaris Dimitris
Published: March 2004

This study examines role conflict, role ambiguity, and job satisfaction among Greek physical education teachers, and the extent to which role conflict and role ambiguity predict job satisfaction. All members of the sample of 61 physical education teachers were employed in Greek “Sport for all” programs. The standard multiple regression analysis shows that role conflict and role ambiguity are significant predictors of job satisfaction. This paper concludes with suggestions directed to the General Secretariat of Sports in Greece with a view to redesigning the work of physical education teachers in “Sport for all” programs.
Costs and benefits of the workaround: inventive solution or costly alternative
Authors: Petrides Lisa A. , McClelland Sara I. , Nodine Thad R.
Published: March 2004

In the current climate of increased accountability in higher education, many colleges and universities are considering ways to improve their collection and analysis of data and information to achieve organizational improvement. While there has been much written about the costs, difficulties, and challenges of implementing new information systems on college campuses, the costs and benefits of maintaining current systems are not well understood. Our research suggests that in a challenging information environment, enterprising individuals – when unable to obtain the data they need from existing information systems – compensate by creating, or participating in, idiosyncratic methods of data collection and management. These informal practices – calledworkarounds– can be seen as both inventive solutions to pressing organizational needs and over time, and costly alternative to a robust and flexible information system.
Teachers’ and principals’ perceptions of the summative evaluation conference: an examination of Model I theories‐in‐use
Authors: Calabrese Raymond L. , Sherwood Kristen , Fast John , Womack Cynthia
Published: March 2004

A research team consisting of doctoral students and their faculty advisor investigated the differences in perceptions, beliefs, and attitudes between school principals and teachers in a United States suburban Midwest school district using a qualitative embedded case study research design. Researchers interviewed all building principals; they invited 80 teachers who received summative evaluations within the previous 18 months to participate in the left‐ and right‐hand column case method, 40 teachers participated; the team also examined district documents related to summative evaluations. Findings indicated that principals and teachers operate in Model I theory‐in‐use.
In search of universal principles of higher education management and applicability to Moldavian higher education system
Authors: Michael Steve O.
Published: March 2004

Focuses on Moldavia, and its task of nation building – a task that depends, in part, on the effectiveness of the nation's educational system– following the demise of the Soviet Union. Provides a brief discussion of the growing importance of higher education, examines the evolution of higher education and management responses to the changing environment, and identifies current management practices in higher education. Concludes with a set of universal principles or characteristics of effective higher education and with an injunction to countries in transition and developing countries to reorient their educational policies in light of these principles.
Course management and students’ expectations: theory‐based considerations
Authors: Buckley M. Ronald , Novicevic Milorad M. , Halbesleben Jonathon R.B. , Harvey Michael
Published: March 2004

This paper proposes a theoretical, yet practical, framework for managing the formation process of students unrealistic expectations in a college course. Using relational contracting theory, alternative teacher interventions, aimed at effective management of students expectations about the course, are described. Also, the formation of the student entitlement process is examined. Finally, a matrix of remedies for effective management of students' unrealistic expectations is proposed. In conclusion, practical implications of the proposed framework for the advancement of teaching scholarship are outlined.
Key steps for success in export markets
Authors: Darling John R. , Seristö Hannu T.
Published: March 2004

This article focuses on a paradigm of ten key steps for successful decision making in export marketing for the European business firm. These ten steps are: analyze market opportunity; assess product potential; establish market entry mode; make a firm commitment; allocate necessary resources; identify technical issues; develop strategic marketing plan; organize operational team; implement marketing strategy; and evaluate and control operations. Tables of basic what, who, and how questions help to guide the reader through the decision‐making process, leading to successful export marketing operations. The article provides a decision‐making paradigm that is useful to top‐level management personnel as well as export managers. This model has been developed by the authors based upon over 25 years of consulting work with European business firms.
Testing the homogeneity of SMEs
Authors: O'Regan Nicholas , Ghobadian Abby
Published: March 2004

The European Commission (EC) is updating the definition of small and medium sized enterprises (SMEs) following widespread consultation. The EC is focusing on a redefinition of the financial ceiling criterion rather than the ceilings in relation to the number of persons employed in categorising SMEs as micro, small or medium. The retention of a ceiling of 250 employees as the overall employment criterion for SMEs has a major drawback in that it assumes that all firms from micro to medium have broadly similar organisational and managerial processes. Some researchers contend that organisational size based on employee numbers is an important underpinning factor in the way these processes are emphasised. The analysis presented indicates that while size is important, it does not have a significant impact on the managerial and organisational processes examined. These findings lend some support for the retention of the existing size criterion in the definition of SMEs.
The connectance model revisited: a tool for manufacturing objective deployment
Authors: Hua Tan Kim , Platts Ken
Published: March 2004

Much has been written about manufacturing strategy and its role in supporting firms in achieving competitive advantage in the marketplace. However, little is available on the process of manufacturing objective deployment, that is, on how to translate a given objective into the choice of action plans. There is a lack of methods to assist managers in identifying the range of alternative actions prior to arriving at a final decision. To address this gap, this paper revisits Burbidge’s connectance model and explains how the concept could be utilised as a tool for manufacturing improvement action plan selection. A software tool, tool for action plan selection was developed based on the concept and tested in a number of industrial case studies. This paper concludes by discussing the implication of this work for managers and academics.
A subset of mouse tracheal epithelial basal cells generates large colonies in vitro
Authors: Schoch Kelly G. , Lori Adriana , Burns Kimberlie A. , Eldred Tracy , Olsen John C. , Randell Scott H.
Published: March 2004

Airway epithelial stem cells are not well characterized. To examine clonal growth potential, we diluted single, viable B6.129S7-Gtrosa26 (Rosa26) mouse tracheal epithelial cells that constitutively express β-galactosidase into non-Rosa26 cells in an air-liquid interface cell culture model; 1.7% of the cells formed colonies of varying size, and, on average, 0.1% of the cells formed large colonies. Thus only a small subset of cells displayed progenitorial capacity suggestive of stem or early transient amplifying cells. Prior studies identified cells with high keratin 5 (K5) promoter activity in specific niches in the mouse trachea and these cells corresponded to the location of bromodeoxyuridine label-retaining cells, thought to be stem cells (Borthwick DW, Shahbazian M, Todd KQ, Dorin JR, and Randell SH, Am J Respir Cell Mol Biol: 24: 662–670, 2001). To explore the hypothesis that stem cells were present in the K5-expressing compartment, we created transgenic mice in which enhanced green fluorescent protein (EGFP) was driven by the K5 promoter. These mice expressed EGFP in most basal cells of the body including a subset of tracheal basal cells apparently located in positions similar to previously identified stem cell niches. Flow cytometrically purified EGFP-positive cells had an overall colony-forming efficiency 4.5-fold greater than EGFP-negative cells, but the ability to generate large colonies was 12-fold greater. Thus adult mouse tracheal epithelial cells with progenitorial capacity sufficient to generate large colonies reside in the basal cell compartment. These studies are a first step toward purification and characterization of airway epithelial stem cells.
Leukocytic cell sources of airway tissue kallikrein
Authors: Lauredo Isabel T. , Forteza Rosanna M. , Botvinnikova Yelena , Abraham William M.
Published: March 2004

Lung tissue kallikrein (TK) is a serine proteinase that putatively plays a role in the pathophysiology of asthma by generating kallidin and bradykinin, mediators that contribute to airway hyperresponsiveness. In previous studies we observed biphasic increases in TK activity in bronchoalveolar lavage fluid following airway allergen challenge in allergic sheep. Although glandular TK is likely a major source of the initial increase in TK, the sources of the late increases in TK that are associated with the development of airway hyperresponsiveness may be dependent on activated resident and recruited inflammatory cells including alveolar macrophages (AMs) and neutrophils (PMNs). These cells increase concomitantly with the late increases in TK activity. To test this hypothesis, we obtained AMs from bronchoalveolar lavage fluid and PMNs and monocytes (precursors of AMs) from sheep blood and determined whether these cells contained TK and whether these same cells could release TK upon activation. Using confocal microscopy, immunocytochemical techniques, and enzyme activity assays, we found that all three cell types contained and secreted TK. All three cell types demonstrated basal release of TK, which could be increased after stimulation with zymosan. In addition, PMNs also released TK in the presence of phorbol ester, suggesting multiple secretory pathways in these cells. Furthermore, we showed that human monocytes also contain and secrete TK. We conclude that in the airways, monocytes, PMNs, and AMs may contribute to increased TK activity. Knowing the sources of TK in the airways could be important in understanding the mechanisms of inflammation that contribute to the pathophysiology of asthma and may help in the development of new therapies to control the disease.
In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations
Authors: Hong Kyung U. , Reynolds Susan D. , Watkins Simon , Fuchs Elaine , Stripp Barry R.
Published: March 2004

The composition of the conducting airway epithelium varies significantly along the proximal to distal axis, with that of the tracheal epithelium exhibiting the greatest complexity. A number of progenitor cells have been proposed to contribute to the maintenance of this cellular diversity both in the steady state and in response to injury. However, individual roles for each progenitor cell type are poorly defined in vivo. The present study was undertaken to investigate the hypothesis that basal cells represent a multipotent progenitor cell type for renewal of the injured tracheal epithelium. To understand their contribution to epithelial repair, mice were exposed to naphthalene to induce airway injury and depletion of the secretory cell progenitor pool. Injury resulted in a rapid induction of cytokeratin 14 (K14) expression among the majority of GSI-B4-reactive cells and associated hyperplasia of basal cells. Restoration of depleted secretory cells occurred after 6 days of recovery and was associated with regression of the basal cell hyperplasia, suggesting a progenitor-progeny relationship. Multipotent differentiation of basal cells was confirmed using a bitransgenic ligand-regulated Cre-loxP reporter approach in which expression of a ubiquitously expressed LacZ reporter was activated within K14-expressing progenitor cells during airway repair. With the use of this approach, it was determined that K14-expressing cells include subsets capable of either multipotent or unipotent differentiation in vivo. We conclude that basal cells have the capacity for restoration of a fully differentiated epithelium.
Activation of p38 MAP kinase by asbestos in rat mesothelial cells is mediated by oxidative stress
Authors: Swain William A. , O'Byrne Kenneth J. , Faux Stephen P.
Published: March 2004

Asbestos fibers are biopersistent particles that are capable of stimulating chronic inflammatory responses in the pleura of exposed individuals. Exposure of pleural mesothelial cells, the progenitor cell of malignant mesothelioma, to asbestos induces an array of cellular responses. The present studies investigated whether the p38 mitogen-activated protein kinase cascade was induced under asbestos-exposed conditions. p38 plays a vital role in the response to stressful stimuli and enables the cell to enter an inflammatory state characterized by cytokine production. Western blot and in vitro kinase assays showed increases in dual phosphorylation and actual activity of p38 after exposure to fibrous and nonfibrous (milled) crocidolite; in contrast, polystyrene beads and iron (III) oxide had no such effects. In common with other asbestos-induced events, this was shown to be an oxidative stress-sensitive effect, inasmuch as preincubation with N-acetyl-l-cysteine or α-tocopherol (vitamin E) ameliorated the effect. The present studies show that p38 activity is important for crocidolite-induced activator protein-1 DNA binding, inasmuch as an inhibitor of p38, SB-203580, reduced this activity. Crocidolite-induced cytotoxicity was also reduced with SB-203580, indicating a role for p38 in asbestos-mediated cell death. Our studies suggest that p38 activity could be a crucial factor in the chronic immune response elicited by asbestos and may represent a target for future pharmacological intervention.
Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cells
Authors: You Yingjian , Huang Tao , Richer Edward J. , Schmidt Jens-Erik Harboe , Zabner Joseph , Borok Zea , Brody Steven L.
Published: March 2004

Factors required for commitment of an undifferentiated airway epithelial cell to a ciliated cell are unknown. Cell ultrastructure analysis indicates ciliated cell commitment activates a multistage program involving synthesis of cilia precursor proteins and assembly of macromolecular complexes. Foxj1 is an f-box transcription factor expressed in ciliated cells and shown to be required for cilia formation by gene deletion in a mouse model. To identify a specific role for foxj1 in directing the ciliated cell phenotype, we evaluated the capacity of foxj1 to induce ciliogenesis and direct cilia assembly. In a primary culture model of wild-type mouse airway epithelial cells, foxj1 expression preceded the appearance of cilia and in cultured foxj1 null cells cilia did not develop. Delivery of foxj1 to polarized epithelial cell lines and primary cultured alveolar epithelial cells failed to promote ciliogenesis. Similarly, delivery of foxj1 to wild-type airway epithelial cells did not enhance the total number of ciliated cells. In contrast, delivery of foxj1 to null cells resulted in the appearance of cilia. Analysis revealed that, in the absence of foxj1, null cells contained cilia precursor basal bodies, indicating prior commitment to ciliogenesis. However, the basal bodies were disorganized within the apical compartment and failed to dock with the apical membrane. Reconstitution of foxj1 in null cells restored normal basal body organization, resulting in axoneme growth. Thus foxj1 functions in late-stage ciliogenesis to regulate programs promoting basal body docking and axoneme formation in cells previously committed to the ciliated cell phenotype.
Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways
Authors: Yu Jane , Astrinidis Aristotelis , Howard Sharon , Henske Elizabeth Petri
Published: March 2004

Lymphangioleiomyomatosis (LAM) is a progressive lung disease affecting almost exclusively women. The reasons for this strong gender predisposition are poorly understood. Renal angiomyolipomas occur in 50–60% of sporadic LAM patients. The smooth muscle cells of pulmonary LAM and renal angiomyolipomas are nearly indistinguishable morphologically. Here, we report the first successful cell culture of a LAM-associated renal angiomyolipoma. The cells carried inactivating mutations in both alleles of the TSC2 gene and expressed estrogen receptor α, estrogen receptor β, and androgen receptor. To elucidate the cellular pathways through which steroid hormones influence LAM pathogenesis, we treated the cells with both estradiol and tamoxifen. Cell growth was stimulated by estradiol, associated with phosphorylation of p44/42 MAPK at 5 min and an increase in c-myc expression at 4 h. Tamoxifen citrate also stimulated cell growth, associated with increased phosphorylation of p44/42 MAPK and expression of c-myc, indicating that tamoxifen has agonist effects on angiomyolipoma cells. This response to tamoxifen in human angiomyolipoma cells differs from prior studies of Eker rat leiomyoma cells, possibly reflecting cell type or species differences in cells lacking tuberin. Our data provide the first evidence that estradiol stimulates the growth of angiomyolipoma cells, that tamoxifen has agonist effects in angiomyolipoma cells, and that estradiol and tamoxifen impact both genomic and nongenomic signaling pathways in angiomyolipoma cells. The responsiveness of angiomyolipoma cells to estradiol may be related to the underlying reasons that LAM affects primarily women.
Mechanisms of alveolar protein clearance in the intact lung
Authors: Hastings Randolph H. , Folkesson Hans G. , Matthay Michael A.
Published: March 2004

Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lung. Various mechanisms have been proposed for clearing alveolar protein, including transport by the mucociliary escalator, intra-alveolar degradation, or phagocytosis by macrophages. However, the most likely processes are endocytosis across the alveolar epithelium, known as transcytosis, or paracellular diffusion through the epithelial barrier. This article focuses on protein transport studies that evaluate these two potential mechanisms in whole lung or animal preparations. When protein concentrations in the air spaces are low, e.g., albumin concentrations <0.5 g/100 ml, protein transport demonstrates saturation kinetics, temperature dependence indicating high energy requirements, and sensitivity to pharmacological agents that affect endocytosis. At higher concentrations, the protein clearance rate is proportional to protein concentration without signs of saturation, inversely related to protein size, and insensitive to endocytosis inhibition. Temperature dependence suggests a passive process. Based on these findings, alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations. Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs by paracellular pathways in the setting of pulmonary edema. Transcytosis may be important in regulating the alveolar milieu under nonpathological circumstances. Alveolar degradation may become important in long-term protein clearance, clearance of insoluble proteins, or under pathological conditions such as immune reactions or acute lung injury.
Induction of CDK inhibitor p21 gene as a new therapeutic strategy against pulmonary fibrosis
Authors: Inoshima Ichiro , Kuwano Kazuyoshi , Hamada Naoki , Yoshimi Michihiro , Maeyama Takashige , Hagimoto Naoki , Nakanishi Yoichi , Hara Nobuyuki
Published: March 2004

Alveolar epithelial cells are known to be present at the primary site of lung damage in pulmonary fibrosis. Apoptosis has been implicated as being involved in epithelial cell damage and pulmonary fibrosis. Because the cyclin-dependent kinase inhibitor p21 induces G1 arrest and DNA repair and because it also prevents apoptosis in some cells, we hypothesized that p21 gene transfer may attenuate bleomycin-induced pulmonary fibrosis in mice, the pathogenesis of which likely involves epithelial cell apoptosis. Human p21 protein was expressed in mouse alveolar epithelial cells at 1–7 days in vitro and was detected predominantly in lung epithelial cells at 1–7 days in vivo after adenoviral transfer of the human p21 gene. Inflammatory cell infiltration and fibrosis had already begun at 7 days in this model. Adenoviral transfer of the human p21 gene at 7 days after intratracheal instillation of bleomycin led to a decrease in the number of apoptotic cells, lung inflammation, and fibrosis at 14 days. Therefore, the forced expression of p21 exerted both anti-apoptotic and anti-fibrotic effects, which would facilitate the ultimate goal of treatment for pulmonary fibrosis.
IL-1β stimulates alveolar fluid absorption in fetal guinea pig lungs via the hypothalamus-pituitary-adrenal gland axis
Authors: Ye Xin , Acharya Reshma , Herbert Jonathan B. , Hamilton Sarah E. , Folkesson Hans G.
Published: March 2004

We tested the hypothesis that interleukin (IL)-1β-induced cortisol synthesis stimulates alveolar fluid clearance in preterm fetuses. IL-1β was administered subcutaneously daily to timed-pregnant guinea pigs for 3 days with and without simultaneous cortisol synthesis inhibition by metyrapone. Fetuses were obtained by abdominal hysterotomy at 61 and 68 days gestation and instilled with isosmolar 5% albumin in the lungs, and alveolar fluid movement was measured over 1 h from the change in alveolar protein concentration. Alveolar fluid clearance was induced at 61 days gestation and stimulated at 68 days gestation by IL-1β, which both were attenuated by cortisol synthesis inhibition. Plasma ACTH and cortisol concentrations were increased by IL-1β at both gestational ages, and metyrapone reduced cortisol concentrations. IL-1β was mostly low or undetectable in both fetal and maternal blood. Prenatal alveolar fluid clearance, when present as well as IL-1β induced, was always propranolol and amiloride sensitive, suggesting that β-adrenoceptor stimulation and amiloride-sensitive Na+channels were critical for fluid absorption. IL-1β increased lung β-adrenoceptor density at gestation day 61, and cortisol synthesis inhibition attenuated the increased β-adrenoceptor density. Epithelial Na+channel and Na+-K+-ATPase subunit expressions were both increased by IL-1β and attenuated by cortisol synthesis inhibition. These results may explain why babies delivered preterm after intrauterine inflammation have a reduced risk of developing severe respiratory distress.
Effects of sham air and cigarette smoke on A549 lung cells: implications for iron-mediated oxidative damage
Authors: Mayo Jonathan J. , Kohlhepp Pete , Zhang Dianzheng , Winzerling Joy J.
Published: March 2004

Inhalation of airborne pollution particles that contain iron can result in a variety of detrimental changes to lung cells and tissues. The lung iron burden can be substantially increased by exposure to cigarette smoke, and cigarette smoke contains iron particulates, as well as several environmental toxins, that could influence intracellular iron status. We are interested in the effects of environmental contaminants on intracellular iron metabolism. We initiated our studies using lung A549 type II epithelial cells as a model, and we evaluated the effects of iron dose and smoke treatment on several parameters of intracellular iron metabolism. We show that iron at a physiological dose stimulates ferritin synthesis without altering the transferrin receptor (TfR) mRNA levels of these cells. This is mediated primarily by a reduction of iron regulatory protein 2. Higher doses of iron reduce iron regulatory protein-1 binding activity and are accompanied by a reduction in TfR mRNA. Thus, for A549 cells, different mechanisms influencing IRP-IRE interaction allow ferritin translation in the presence of TfR mRNA to provide for iron needs and yet prevent excessive iron uptake. More importantly, we report that smoke treatment diminishes ferritin levels and increases TfR mRNA of A549 cells. Ferritin serves as a cytoprotective agent against oxidative stress. These data suggest that exposure of lung cells to low levels of smoke as are present in environmental pollutants could result in reduced cytoprotection by ferritin at a time when iron uptake is sustained, thus enhancing the possibility of lung damage by iron-mediated oxidative stress.
Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4
Authors: Bozinovski Steven , Jones Jessica , Beavitt Sarah-Jane , Cook Andrew D. , Hamilton John A. , Anderson Gary P.
Published: March 2004

The innate immune inflammatory response to lipopolysaccharide (LPS, an endotoxin) is essential for lung host defense against infection by gram-negative bacteria but is also implicated in the pathogenesis of some lung diseases. Studies on genetically altered mice implicate granulocyte-macrophage colony-stimulating factor (GM-CSF) in lung responses to LPS; however, the physiological effects of GM-CSF neutralization are poorly characterized. We performed detailed kinetic and dose-response analyses of the lung inflammation response to LPS in the presence of the specific GM-CSF-neutralizing antibody 22E9. LPS instilled into the lungs of BALB/c mice induced a dose-dependent inflammation comprised of intense neutrophilia, macrophage infiltration and proliferation, TNF-α and matrix metalloproteinase release, and macrophage inflammatory protein-2 induction. The neutralization of anti-GM-CSF in a dose-dependent fashion suppressed these inflammatory indexes by ≤85% when given before or after LPS or after repeat LPS challenges. Here we report for the first time that the physiological expression of Toll-like receptor-4 in lung is reduced by anti-GM-CSF. We observed that lower Toll-like receptor-4 expression correlated with a similar decline in peak TNF-α levels in response to endotoxin. Consequently, sustained expression of key inflammatory mediators over 24 h was reduced. These data expand the understanding of the contribution of GM-CSF to innate immune responses in lung and suggest that blocking GM-CSF might benefit some lung diseases where LPS has been implicated in etiology.
Glucocorticoid inhibition ofSP-Agene expression in lung type II cells is mediated via the TTF-1-binding element
Authors: Alcorn Joseph L. , Islam Kazi N. , Young Pampee P. , Mendelson Carole R.
Published: March 2004

Induction of surfactant protein-A ( SP-A) gene expression in fetal lung type II cells by cAMP and IL-1 is mediated by increased binding of thyroid transcription factor-1 (TTF-1) and NF-κB proteins p50 and p65 to the TTF-1-binding element (TBE) at -183 bp. In type II cell transfections, dexamethasone (Dex) markedly inhibits cAMP-induced expression of rabbit SP-A:human growth hormone ( hGH) fusion genes containing as little as ∼300 bp of the SP-A 5′-flanking sequence. Dex inhibition is blocked by RU-486, suggesting a role of the glucocorticoid receptor (GR). The present study was undertaken to define the mechanisms for GR inhibition of SP-A expression. Cotransfection of primary cultures of type II cells with a GR expression vector abrogated cAMP induction of SP-A promoter activity while, at the same time, causing a 60-fold induction of cotransfected mouse mammary tumor virus ( MMTV) promoter. In lung cells transfected with a fusion gene containing three TBEs fused to the basal SP-A promoter, Dex prevented the stimulatory effect of IL-1 on TTF-1 induction of SP-A promoter activity, suggesting that the GR inhibits SP-A promoter activity through the TBE. In gel shift assays using nuclear extracts from human fetal type II cells cultured in the absence or presence of cAMP, Dex markedly reduced binding of nuclear proteins to the TBE and blocked the stimulatory effect of cAMP on TBE-binding activity. Our finding that Dex increased expression of the NF-κB inhibitory partner IκB-α suggests that the decrease in TBE-binding activity may be caused, in part, by GR inhibition of NF-κB interaction with this site.
Hypoxia-induced acute lung injury in murine models of sickle cell disease
Authors: Pritchard Kirkwood A. , Ou Jingsong , Ou Zhijun , Shi Yang , Franciosi James P. , Signorino Paul , Kaul Sushma , Ackland-Berglund Cathleen , Witte Karin , Holzhauer Sandra , Mohandas Narla , Guice Karen S. , Oldham Keith T. , Hillery Cheryl A.
Published: March 2004

Vaso-occlusive events are the major source of morbidity and mortality in sickle cell disease (SCD); however, the pathogenic mechanisms driving these events remain unclear. Using hypoxia to induce pulmonary injury, we investigated mechanisms by which sickle hemoglobin increases susceptibility to lung injury in a murine model of SCD, where mice either exclusively express the human α/sickle β-globin (hαβS) transgene (SCD mice) or are heterozygous for the normal murine β-globin gene and express the hαβStransgene (mβ+/-, hαβS+/-; heterozygote SCD mice). Under normoxia, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine, and cGMP than controls (C57BL/6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in lungs with a greater content of XO and nitrotyrosine. Under normoxia, the association of heat shock protein 90 (HSP90) with endothelial nitric oxide synthase (eNOS) in lungs of SCD and heterozygote SCD mice was decreased compared with the levels of association in lungs of controls. Hypoxia further decreased association of HSP90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the control lungs. Pretreatment of rat pulmonary microvascular endothelial cells in vitro with xanthine/XO decreased A-23187-stimulated nitrite + nitrate production and HSP90 interactions with eNOS. These data support the hypotheses that hypoxia increases XO release from ischemic tissues and that the local increase in XO-induced oxidative stress can then inhibit HSP90 interactions with eNOS, decreasing ·NO generation and predisposing the lung to vaso-occlusion.
Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle
Authors: Wang Jian , Shimoda L. A. , Sylvester J. T.
Published: March 2004

Mammalian homologs of transient receptor potential (TRP) genes in Drosophila encode TRPC proteins, which make up cation channels that play several putative roles, including Ca2+ entry triggered by depletion of Ca2+ stores in endoplasmic reticulum (ER). This capacitative calcium entry (CCE) is thought to replenish Ca2+ stores and contribute to signaling in many tissues, including smooth muscle cells from main pulmonary artery (PASMCs); however, the roles of CCE and TRPC proteins in PASMCs from distal pulmonary arteries, which are thought to be the major site of pulmonary vasoreactivity, remain uncertain. As an initial test of the possibility that TRPC channels contribute to CCE and Ca2+ signaling in distal PASMCs, we measured [Ca2+]i by fura-2 fluorescence in primary cultures of myocytes isolated from rat intrapulmonary arteries (>4th generation). In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 μM) and nifedipine (5 μM) to deplete ER Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i whereas MnCl2 (200 μM) quenched fura-2 fluorescence, indicating CCE. SKF-96365, LaCl3, and NiCl2, blocked CCE at concentrations that did not alter Ca2+ responses to 60 mM KCl (IC50 6.3, 40.4, and 191 μM, respectively). RT-PCR and Western blotting performed on RNA and protein isolated from distal intrapulmonary arteries and PASMCs revealed mRNA and protein expression for TRPC1, -4, and -6, but not TRPC2, -3, -5, or -7. Our results suggest that CCE through TRPC-encoded Ca2+ channels could contribute to Ca2+ signaling in myocytes from distal intrapulmonary arteries.
Secretion of lactoferrin and lysozyme by cultures of human airway epithelium
Authors: Dubin R. F. , Robinson S. K. , Widdicombe J. H.
Published: March 2004

Lactoferrin and lysozyme are important antimicrobial compounds of airway surface liquid, derived predominantly from serous cells of submucosal glands but also from surface epithelium. Here we compared release of these compounds from the following human cell cultures: primary cultures of tracheal epithelium (HTE), Calu-3 cells (a lung adenocarcinoma cell line frequently used as a model of serous gland cells), 16HBE14o- cells (an SV40 transformed line from airway surface epithelium), T84 cells (a colon carcinoma cell line), and human foreskin fibroblasts (HFF). For lysozyme, baseline secretory rates were in the order Calu-3 > 16HBE14o- > HTE ≈ T84 > HFF = 0; for lactoferrin, the only cell type showing measurable release was HTE; for mucus, HTE > Calu-3 > 16HBE14o- ≈ T84 > HFF = 0. A wide variety of neurohumoral agents and inflammatory stimuli was without effect on lactoferrin and lysozyme release from HTE or Calu-3 cells, although forskolin did stimulate secretion of water and lysozyme from Calu-3 cells. However, the concentration of lysozyme in the forskolin-induced secretions was much less than in airway gland secretions. Thus our data cast doubt on the utility of Calu-3 cells as a model of airway serous gland cells but do suggest that HTE could prove highly suitable for studies of mucin synthesis and release.
Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung
Authors: Lian Xuemei , Yan Cong , Yang Li , Xu Yan , Du Hong
Published: March 2004

The functional roles of neutral lipids are poorly understood in the lung. Blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) resulted in a high level of neutrophil influx in the lungs as early as 2 mo of age. Bronchoalveolar macrophages appeared foamy and gradually increased in number with age progression. Affymetrix GeneChip array analysis of lung mRNA showed increased levels of proinflammatory cytokine (including IL-1β, IL-6, and TNF-α) and matrix metalloproteinase (including MMP-8, MMP-9, and MMP-12) expression in lal-/- mice. With age progression, some areas of lal-/- mice developed severe abnormal cell proliferation and alveolar remodeling. In other areas, alveolar destruction (i.e., emphysema) was observed. In addition, Clara cell hypertrophy and hyperplasia developed in conducting airways. The pathophysiological phenotypes in the lal-/- mouse lungs became more severe with increasing age. The studies support the concept that neutral lipid metabolites play essential roles in pulmonary homeostasis, inflammatory responses, remodeling, and injury repair.
Myosin light chain phosphorylation and pulmonary endothelial cell hyperpermeability in burns
Authors: Tinsley John H. , Teasdale Nicole R. , Yuan Sarah Y.
Published: March 2004

Major cutaneous burns result in not only localized tissue damage but broad systemic inflammation causing organ system damage distal to the burn site. It is well recognized that many problems result from the release of inflammatory mediators that target vascular endothelial cells, causing organ dysfunction. The pulmonary microvessels are particularly susceptible to functional abnormalities as a direct consequence of exposure to burn-induced inflammatory mediators. Traditional therapeutic intervention is quite often ineffective in treating burn patients suffering from systemic problems. A possible explanation for this ineffectiveness may be that because so many mediators are released, supposedly activating numerous signaling cascades that interact with each other, targeting of upstream factors in these cascades on an individual basis becomes futile. Therefore, if an end-point effector responsible for endothelial dysfunction following burn injury could be identified, it may present a target for intervention. In this study, we identified phosphorylation of myosin light chain (MLC) as a required element of burn plasma-induced hyperpermeability across rat lung microvascular endothelial cell monolayers. In addition, pharmacological inhibition of myosin light chain kinase (MLCK) and Rho kinase as well as transfection of MLCK-inhibiting peptide blocked actin stress fiber formation and MLC phosphorylation in response to burn plasma. The results suggest that blocking MLC phosphorylation may provide therapeutic intervention in burn patients with the goal of alleviating systemic inflammation-induced endothelial dysfunction.