Role of myeloid Hif-1α in acute lung injury

Acute Lung Injury, characterised clinically as the Acute Respiratory Distress Syndrome is a catastrophic response to a range of pulmonary and non-pulmonary insults. Despite much work the key mechanisms involved in generating the exaggerated immune response that results in lung injury are not completely understood. Hypoxia-inducible factor-1 has been shown to be a key transcription factor in the myeloid cell response to inflammatory signals. The aims of this thesis were to develop a model of acute lung injury and to study the role of Hif-1 in the generation of lung injury in this model. A model of direct pulmonary injury as a result of intratracheal instillation of endotoxin is described. Using this model the role of myeloid cell Hif-1α was characterised using a myeloid cell specific conditional knockout system. The injury in Hif-1α deficient mice was quantitatively similar to the injury seen in wild type animals over a range of time points. However, the quality of the injury, assessed by a measure of nitric oxide mediated damage was reduced. The in vivo data were supported by in vitro studies using a murine macrophage cell line which showed that manipulation of the cellular oxygen tension in the presence of endotoxin alters the ability of the cell to generate nitric oxide. Furthermore, pharmacological manipulation of cellular Hif-1 levels by Dimethyloxallyl Glycine (DMOG) in the macrophage cell increased the generation of nitric oxide in response to endotoxin by altering the expression of a number of the isoforms of Nitric Oxide Synthase. In a final set of experiments the response to intratracheal endotoxin was modulated in mice by the concurrent administration of DMOG. As expected the qualitative response to endotoxin was similar but the NO mediated damage was enhanced in the animals administered DMOG. Manipulation of Hif-1 may have a role in the therapy of lung injury by altering the characteristics of the response

Windows and mirrors: reflections of a module team teaching the arts in nurse education.

The five-year experience of a group of nursing lecturers teaching the expressive arts within a Scottish degree programme is outlined and discussed. The place of the arts is contextualised within curriculum developments and module content, sequencing, thematic development, mode of delivery, assessment, student evaluation and pedagogical approaches are all addressed. Relationship to practice is discussed in terms of the art of nursing, reflection, ethics and spirituality. Future developments are discussed in terms of drawing upon the wider resources of the humanities, rather than merely expressivist sources of art. The paper concludes by encouraging the teaching of the arts in nurse education to remain responsive to practice issues and to consideration of students' learning needs

Ventilator-associated pneumonia: pathobiological heterogeneity and diagnostic challenges.

Ventilator-associated pneumonia (VAP) affects up to 20% of critically ill patients and induces significant antibiotic prescription pressure, accounting for half of all antibiotic use in the ICU. VAP significantly increases hospital length of stay and healthcare costs yet is also associated with long-term morbidity and mortality. The diagnosis of VAP continues to present challenges and pitfalls for the currently available clinical, radiological and microbiological diagnostic armamentarium. Biomarkers and artificial intelligence offer an innovative potential direction for ongoing future research. In this Review, we summarise the pathobiological heterogeneity and diagnostic challenges associated with VAP

Always Consider the Possibility of Opioid Induced Respiratory Depression in Patients Presenting with Hypercapnic Respiratory Failure Who Fail to Improve as Expected with Appropriate Therapy

Hypercapnic respiratory failure is a frequently encountered medical emergency. Two common causes are acute exacerbations of chronic obstructive pulmonary disease (COPD) and as a side effect of opioids. The two causes may coexist leading to diagnostic confusion and consequent delay in optimal management. We report a case of what was initially thought to be an exacerbation of COPD. The patient failed to improve with treatment as expected which led to the empirical administration of naloxone resulting in a dramatic reversal of her respiratory failure. The patient was subsequently discovered to be taking regular dihydrocodeine for chronic back pain

Case Report Always Consider the Possibility of Opioid Induced Respiratory Depression in Patients Presenting with Hypercapnic Respiratory Failure Who Fail to Improve as Expected with Appropriate Therapy

Hypercapnic respiratory failure is a frequently encountered medical emergency. Two common causes are acute exacerbations of chronic obstructive pulmonary disease (COPD) and as a side effect of opioids. The two causes may coexist leading to diagnostic confusion and consequent delay in optimal management. We report a case of what was initially thought to be an exacerbation of COPD. The patient failed to improve with treatment as expected which led to the empirical administration of naloxone resulting in a dramatic reversal of her respiratory failure. The patient was subsequently discovered to be taking regular dihydrocodeine for chronic back pain

Role of myeloid Hif-1α in acute lung injury

Acute Lung Injury, characterised clinically as the Acute Respiratory Distress Syndrome is a catastrophic response to a range of pulmonary and non-pulmonary insults. Despite much work the key mechanisms involved in generating the exaggerated immune response that results in lung injury are not completely understood. Hypoxia-inducible factor-1 has been shown to be a key transcription factor in the myeloid cell response to inflammatory signals. The aims of this thesis were to develop a model of acute lung injury and to study the role of Hif-1 in the generation of lung injury in this model. A model of direct pulmonary injury as a result of intratracheal instillation of endotoxin is described. Using this model the role of myeloid cell Hif-1α was characterised using a myeloid cell specific conditional knockout system. The injury in Hif-1α deficient mice was quantitatively similar to the injury seen in wild type animals over a range of time points. However, the quality of the injury, assessed by a measure of nitric oxide mediated damage was reduced. The in vivo data were supported by in vitro studies using a murine macrophage cell line which showed that manipulation of the cellular oxygen tension in the presence of endotoxin alters the ability of the cell to generate nitric oxide. Furthermore, pharmacological manipulation of cellular Hif-1 levels by Dimethyloxallyl Glycine (DMOG) in the macrophage cell increased the generation of nitric oxide in response to endotoxin by altering the expression of a number of the isoforms of Nitric Oxide Synthase. In a final set of experiments the response to intratracheal endotoxin was modulated in mice by the concurrent administration of DMOG. As expected the qualitative response to endotoxin was similar but the NO mediated damage was enhanced in the animals administered DMOG. Manipulation of Hif-1 may have a role in the therapy of lung injury by altering the characteristics of the response.EThOS - Electronic Theses Online ServiceGBUnited Kingdo