To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.
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http://dx.doi.org/10.1159/000091126 | DOI Listing |
Neurol Neuroimmunol Neuroinflamm
March 2025
Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney.
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Department of Pain Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
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January 2025
Department of Ocean Science, Iranian National Institute for Oceanography and Atmospheric Science, Tehran, Iran.
In recent years, despite significant advances in preconcentration and preparation techniques that have led to efficient recovery and accurate measurement of target compounds. There is still a need to develop adsorbents with unique and efficient features such as high pore volume and surface area, reactivity, easy synthesis, low toxicity, and compatibility with the environment, which increase the adsorption capacity and increase extraction efficiency. Semiconductor nanocrystals called quantum dots (QDs) with a size of less than 10 nm are three-dimensional nanoparticles with a spherical, rod, or disc structure that have significant potential in extraction as adsorbents due to their excellent properties such as low toxicity, reactivity, environmental friendliness, and hydrophilic and hydrophobic interactions.
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December 2024
Department of Pharmacy, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China.
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Alzheimers Dement (Amst)
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Neurochemistry Neurocode USA Inc Bellingham USA.
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