Influence of inflammation and of stage of lung development on the development of neonatal lung injury

Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term morbidity in prematurely born infants. Pulmonary inflammation, and abnormal alveolar and vascular development of the lung are histological characteristics of BPD. Interleukin (IL)-1β is a central cytokine in inflammation. Increased concentration of IL-1β in amniotic fluid or postnatally in the lungs of newborn infants is associated with the development of BPD. Bitransgenic mice expressing human (h)IL-1β in the lung epithelium develop a BPD-like illness. The aims of this thesis were to study the development of hIL-1β-induced lung disease in this transgenic mouse model in order to find factors regulating the development of the disease and to analyze gastric fluid in order to identify premature infants who are at high risk of developing BPD. Since preterm labor is often preceded by intrauterine infection, the majority of infants born at less than 30 weeks of gestation have been exposed to antenatal inflammation. To study the effect of maternal inflammation on fetal inflammatory responses, hIL-1β expression was induced in pregnant dams and their hIL-1β-expressing offspring were compared to those of control dams. In bitransgenic dams, the production of hIL-1β starts before the fetuses start producing hIL-1β. The results show that maternal hIL-1β production preceding fetal hIL-1β production causes silencing of inflammatory genes in the lungs of bitransgenic offspring and protects them against hIL-1β-induced lung injury. The mammalian lung undergoes five distinct developmental stages, the embryonic, the pseudoglandular, the canalicular, the saccular, and the alveolar stage. Children developing BPD are typically born in the early saccular stage. Expression of hIL-1β was induced in fetal and newborn mice at different time points in order to study the sensitivity of the lung to hIL-1β-induced injury during the different developmental stages. The results show that hIL-1β production in the lungs during the mid-saccular stage, but not in the late canalicular-early saccular or late saccular-alveolar stages, is sufficient to cause a BPD-like illness with abnormal lung development, inflammation, and increased mortality. Usually tracheal aspirates are used to detect inflammation in the newborn lung. Obtaining tracheal aspirates from premature infants requires intubation, an invasive procedure that may promote the development of BPD. Gastric aspirate samples can be retrieved from premature infants at the time of routine placement of a nasogastric tube shortly after birth. The results show that levels of inflammatory proteins in the gastric aspirates are strongly increased in fetuses exposed to clinical chorioamnionitis and are associated with the development of BPD. These results suggest that gastric aspirate can be used instead of more invasive methods to assess the exposure of premature infants to inflammation and to assess the impact of perinatal inflammation on neonatal outcome

Att leda evidensbaserad vård : Olika uppfattningar hos ledare - En fenomenografisk studie

SAMMANFATTNING Bakgrund: Evidensbaserad vård inom hälso- och sjukvården baseras på bästa tillgängliga kunskap och gynnar patient och samhälle. Trots sjuksköterskors positiva inställning till evidensbaserad vård tillämpas det sällan i praktiken och hälso- och sjukvårdsorganisationer har bristande beredskap för evidensbaserad vård. En hög vårdkvalitet och god patientsäkerhet grundar sig i kunskap och kompetens, och en ökad kunskap i evidensbaserad vård ökar tillämpningen. Organisationen och ledarskapet skapar förutsättningar för evidensbaserad vård och stödet från ledare har betydelse för tillämpningen av evidensbaserad vård. Syfte: Syftet var att utforska uppfattningen av att leda evidensbaserad vård på enheter inom slutenvården där kirurgiska patienter förekommer. Metod: Sex ledare inom slutenvården intervjuades individuellt utifrån en semistrukturerad frågeguide. Insamlade data analyserades med fenomenografisk metod. Resultat: Resultatet beskriver tre kategorier med uppfattningar av att leda evidensbaserad vård där fokus riktas mot evidensbaserad vård som något komplext, viktigt och utmanande där de olika uppfattningarna resulterar i ledarskap utan struktur; ledare som genom riktlinjer och rutiner skapar förutsättningar för personalen att arbeta evidensbaserat; och ledare som med en aktiv roll som underlättare håller projekten levande. Slutsats: Att vara ledare inom slutenvården innebär inte med automatik att man ser sig som en ledare av evidensbaserad vård. För att kunna leda evidensbaserad vård behövs kunskap om syftet och innebörden hos alla som har ledande positioner i en organisation, eftersom organisationen har betydelse för vilka förutsättningar som ges ledaren att leda evidensbaserad vård.ABSTRACT Background: Evidence-based practice within healthcare implies that healthcare builds upon best available knowledge and promotes both patient and society. Nurses hold a positive attitude towards evidence-based practice but seldom carries it out and healthcare organizations readiness for evidence-based practice is lacking. High quality care and patient safety constitutes in knowledge and competence, and an increased knowledge in evidencebased practice also increases its implementation. Organization and leadership creates prerequisites for evidence-based practice and the support from leaders is of importance for the appliance. Aim: The aim of this study was to explore the understanding of leading evidencebased practice within inpatient care in wards with surgical patients. Method: Six leaders within inpatient care were individually interviewed using a semi-structured question guide. Collected data were analyzed using a phenomenographic approach. Results: The results present three categories with ways of understanding leading evidence-based practice as something complex, important and challenging. Leading evidence-based practice can be summarized in a set of understandings where the leaders lead without structure, through already existing guidelines and routines where the leaders are responsible for the conditions of their personnel to be able to apply evidence-based practice, and finally as leaders with active roles being the facilitators who keep projects alive. Conclusion: Being a leader doesn’t necessarily implies seeing yourself as a leader of evidence-based practice. To be able to lead evidence-based practice the purpose and meaning of it requires knowledge of everyone with leading positions in an organization, because the organization brings prerequisites for the leaders to lead evidence-based practice

Att leda evidensbaserad vård : Olika uppfattningar hos ledare - En fenomenografisk studie

SAMMANFATTNING Bakgrund: Evidensbaserad vård inom hälso- och sjukvården baseras på bästa tillgängliga kunskap och gynnar patient och samhälle. Trots sjuksköterskors positiva inställning till evidensbaserad vård tillämpas det sällan i praktiken och hälso- och sjukvårdsorganisationer har bristande beredskap för evidensbaserad vård. En hög vårdkvalitet och god patientsäkerhet grundar sig i kunskap och kompetens, och en ökad kunskap i evidensbaserad vård ökar tillämpningen. Organisationen och ledarskapet skapar förutsättningar för evidensbaserad vård och stödet från ledare har betydelse för tillämpningen av evidensbaserad vård. Syfte: Syftet var att utforska uppfattningen av att leda evidensbaserad vård på enheter inom slutenvården där kirurgiska patienter förekommer. Metod: Sex ledare inom slutenvården intervjuades individuellt utifrån en semistrukturerad frågeguide. Insamlade data analyserades med fenomenografisk metod. Resultat: Resultatet beskriver tre kategorier med uppfattningar av att leda evidensbaserad vård där fokus riktas mot evidensbaserad vård som något komplext, viktigt och utmanande där de olika uppfattningarna resulterar i ledarskap utan struktur; ledare som genom riktlinjer och rutiner skapar förutsättningar för personalen att arbeta evidensbaserat; och ledare som med en aktiv roll som underlättare håller projekten levande. Slutsats: Att vara ledare inom slutenvården innebär inte med automatik att man ser sig som en ledare av evidensbaserad vård. För att kunna leda evidensbaserad vård behövs kunskap om syftet och innebörden hos alla som har ledande positioner i en organisation, eftersom organisationen har betydelse för vilka förutsättningar som ges ledaren att leda evidensbaserad vård.ABSTRACT Background: Evidence-based practice within healthcare implies that healthcare builds upon best available knowledge and promotes both patient and society. Nurses hold a positive attitude towards evidence-based practice but seldom carries it out and healthcare organizations readiness for evidence-based practice is lacking. High quality care and patient safety constitutes in knowledge and competence, and an increased knowledge in evidencebased practice also increases its implementation. Organization and leadership creates prerequisites for evidence-based practice and the support from leaders is of importance for the appliance. Aim: The aim of this study was to explore the understanding of leading evidencebased practice within inpatient care in wards with surgical patients. Method: Six leaders within inpatient care were individually interviewed using a semi-structured question guide. Collected data were analyzed using a phenomenographic approach. Results: The results present three categories with ways of understanding leading evidence-based practice as something complex, important and challenging. Leading evidence-based practice can be summarized in a set of understandings where the leaders lead without structure, through already existing guidelines and routines where the leaders are responsible for the conditions of their personnel to be able to apply evidence-based practice, and finally as leaders with active roles being the facilitators who keep projects alive. Conclusion: Being a leader doesn’t necessarily implies seeing yourself as a leader of evidence-based practice. To be able to lead evidence-based practice the purpose and meaning of it requires knowledge of everyone with leading positions in an organization, because the organization brings prerequisites for the leaders to lead evidence-based practice

Maternal IL-1β Production Prevents Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia

Little is known about the influence of maternal inflammation on neonatal outcome. Production of IL-1β in the lungs of newborn infants is associated with bronchopulmonary dysplasia. Using bitransgenic (bi-TG) mice in which human (h) IL-1β is expressed with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter, we have shown that hIL-1β expression causes a bronchopulmonary dysplasia–like illness in infant mice. To study the hypothesis that maternal hIL-1β production modifies the response of the newborn to hIL-1β, doxycycline was administered to bi-TG and control dams from Embryonic Day 0, inducing production of hIL-1β by the bi-TG dams before hIL-1β production started in their bi-TG fetuses, or from Embryonic Day 15, inducing simultaneous production of hIL-1β by both the bi-TG dams and their bi-TG fetuses. In addition to the lungs, hIL-1β was expressed at low levels in the uteri of bi-TG dams. Maternal inflammation preceding fetal inflammation increased the survival and growth of hIL-1β–expressing pups, enhanced alveolarization, and protected the airways against remodeling and goblet cell hyperplasia. Maternal hIL-1β production preceding fetal hIL-1β production caused silencing of several inflammatory genes, including CXC and CC chemokines, murine IL-1β, serum amyloid A3, and Toll-like receptors 2 and 4, and suppressed the expression of chitinase-like lectins Ym1 and Ym2 in the lungs of infant mice. Maternal inflammation protects the newborn against subsequent hIL-1β–induced lung inflammation and injury. In contrast, induction of hIL-1β production simultaneously in bi-TG dams and their fetuses offered no protection against inflammatory lung disease in the neonate

Lung retention by lysosomal trapping of inhaled drugs can be predicted in vitro with lung slices

Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled β-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled β-adrenergic bronchodilators are prolonged

Inflammatory cytokines in gastric fluid at birth and the development of bronchopulmonary dysplasia

Aim:  To assess whether the levels of inflammatory and anti-inflammatory proteins in gastric fluid of premature infants shortly after birth are associated with the development of bronchopulmonary dysplasia (BPD). Methods:  Gastric fluid retrieved within 1 h of birth of premature infants (gestational age <29 weeks) was analysed for interleukin (IL)-8, growth-related oncogene (Gro)-α, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IL-1β and Clara cell secretory protein with ELISA. Results:  Of 51 enrolled infants, 86% had BPD. Of these, 54% had mild BPD, 30% had moderate BPD and 16% had severe BPD. Clinical chorioamnionitis was associated with high levels of IL-8, Gro-α, Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) and IL-1β in gastric fluid. Gastric fluid levels of IL-8, Gro-α, ENA-78 and IL-1β were higher in infants with moderate or severe BPD than in those with no or mild BPD. Ligation of the patent ductus arteriosus was associated with the development of moderate or severe BPD. These associations were no longer significant after adjustment for gestational age. Conclusion:  The levels of inflammatory mediators in gastric fluid samples retrieved soon after birth from intubated or nonintubated infants can be used to assess the infants' perinatal exposure to inflammatory mediators and its association with neonatal outcome

Mechanisms of a sustained anti-inflammatory drug response in alveolar macrophages unraveled with mathematical modeling

Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g. asthma and atherosclerosis. Anti-inflammatory drugs come with side-effects which may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still: a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, Dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism - a slow release of Dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data, and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development, to find sustained anti-inflammatory responses and fewer side effects

Uncovering the regional localization of inhaled salmeterol retention in the lung

Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease

Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors

Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS. Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls. Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD. Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms