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Title: The regulation of interleukin-8 from macrophages by acute hypoxia and hyperoxia : a role in the pathogenesis of the acute respiratory distress syndrome (ARDS)
Author: Hirani, Nikhil A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Adequate oxygenation is a critical requirement for normal cellular function in humans. In patients with conditions such as major trauma, sepsis and aspiration injury there is often significant local and widespread tissue hypoxia as a consequence of inadequate oxygen supply or impaired oxygen utilisation. In this thesis, the role of acute hypoxia and hyperoxia were investigated in a novel animal model of acute lung injury. Bronchoscopic instillation of HC1 acid in an anaesthetised, ventilated rabbit resulted in reproducible acute neutrophilic lung injury in the instilled lobe. The contra-lateral lung acted as a site of potential indirect lung injury. Systemic hypoxaemia was induced by reduction in the inspiratory oxygen fraction. Compared to normoxic controls (arterial PaO2 ~ 11 KPa), acute hypoxia (PaO2 ~ 5 KPa) for up to 2 hours increased intrapulmonary IL-8 mRNA, but not protein expression in the acid-injured lung. Delivery of 100% oxygen for 2 hours (PaO2 ~ 60 KPa) following acute hypoxia, increased both intrapulmonary IL-8 mRNA and IL-8 protein levels. The increase in IL-8 protein was attenuated if the reoxygenation phase was controlled to return arterial PO2 to normoxic levels (~ 11 KPa). Acute hypoxia/hyperoxia may represent a potential mechanism by which intrapulmonary IL-8 levels are rapidly raised in patients at-risk of ARDS. In human blood monocyte derived macrophages, it was shown that acute hypoxia alone rapidly upregulated IL-8 gene expression. A number of other proinflammatory cytokines were conversely down regulated by hypoxia. The IL-8 increase occurred in association with raised nuclear levels of AP-1 and C/EBP-β, but not NF-κB. Hypoxia induced expression of the transcription factor HIF-1α. However cobalt chloride and desferroxamine, HIF-1α-inducing hypoxia mimics, did not upregulate IL-8, suggesting that IL-8 regulation was HIF-1 independent. Both the pattern of chemokine expression and transcription factor activation with hypoxia differed from that induced by lipopolysaccharide (LPS), an archetypal pathogenic stimulus.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available