The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).
BACKGROUND: The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as a...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2001
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| _version_ | 1797082704426041344 |
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| author | Hirani, N Antonicelli, F Strieter, R Wiesener, MS Ratcliffe, P Haslett, C Donnelly, S |
| author_facet | Hirani, N Antonicelli, F Strieter, R Wiesener, MS Ratcliffe, P Haslett, C Donnelly, S |
| author_sort | Hirani, N |
| collection | OXFORD |
| description | BACKGROUND: The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation. MATERIALS AND METHODS: Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay. RESULTS: In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin. CONCLUSIONS: Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS. |
| first_indexed | 2024-03-07T01:31:33Z |
| format | Journal article |
| id | oxford-uuid:93c852e5-890e-45ae-90bc-bf1c5ac32129 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:31:33Z |
| publishDate | 2001 |
| record_format | dspace |
| spelling | oxford-uuid:93c852e5-890e-45ae-90bc-bf1c5ac321292022-03-26T23:34:36ZThe regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:93c852e5-890e-45ae-90bc-bf1c5ac32129EnglishSymplectic Elements at Oxford2001Hirani, NAntonicelli, FStrieter, RWiesener, MSRatcliffe, PHaslett, CDonnelly, SBACKGROUND: The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation. MATERIALS AND METHODS: Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay. RESULTS: In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin. CONCLUSIONS: Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS. |
| spellingShingle | Hirani, N Antonicelli, F Strieter, R Wiesener, MS Ratcliffe, P Haslett, C Donnelly, S The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title | The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title_full | The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title_fullStr | The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title_full_unstemmed | The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title_short | The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). |
| title_sort | regulation of interleukin 8 by hypoxia in human macrophages a potential role in the pathogenesis of the acute respiratory distress syndrome ards |
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