| 1. |
- Bergquist, Maria, et al.
(författare)
-
Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
- 2013
-
Ingår i: Journal of Infection. - : Elsevier BV. - 0163-4453 .- 1532-2742. ; 67:6, s. 574-583
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. Methods: Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. Results: GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). Conclusion: Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock.
|
|
| 2. |
|
|
| 3. |
- Bergquist, Maria, et al.
(författare)
-
Glucocorticoid receptor expression and binding capacity in patients with burn injury.
- 2016
-
Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 1399-6576 .- 0001-5172. ; 60:2
-
Tidskriftsartikel (refereegranskat)abstract
- Burn injuries are associated with strong inflammation and risk of secondary sepsis which both may affect the function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in leucocytes from patients admitted to a tertiary burn center.
|
|
| 4. |
- Bergquist, Maria, et al.
(författare)
-
Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock
- 2014
-
Ingår i: Journal of Infection. - : Elsevier BV. - 0163-4453 .- 1532-2742. ; 69:2, s. 113-122
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: It remains unclear whether glucocorticoid treatment can improve the outcome of sepsis. The aim of the present study was to investigate if glucocorticoid receptor (GR) expression and function is impaired in lipopolysaccharide (LPS) induced shock, and whether the time point for start of glucocorticoid treatment affects the outcome.METHODS: Male C57BL/6J mice were administered LPS i.p. and GR expression and binding ability in blood and spleen leukocytes were analysed by flow cytometry. GR translocation was analysed using Image Stream technique. The effect of dexamethasone treatment started 2 h before or 2, 12 or 36 h after LPS administration on survival was studied.RESULTS: Despite increased GR expression in neutrophils after LPS administration, the GR binding capacity was reduced. In addition, GR translocation was decreased in neutrophils and T lymphocytes from endotoxic mice at 12 h compared to control animals. Dexamethasone treatment improved survival only when started early (2 h) after LPS administration.CONCLUSION: The decreased glucocorticoid responsiveness displayed by neutrophils, in combination with their increased numbers, may explain why survival is increased only when dexamethasone treatment is given early during LPS induced shock.
|
|
| 5. |
- Bergquist, Maria
(författare)
-
Glucocorticoid receptors in severe inflammation : Experimental and clinical studies
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Septic shock is one of the most common causes of mortality in intensive care, in spite of antibiotic treatment. Glucocorticoid treatment can be used to blunt an overwhelming immune response in severe inflammation. The varying effects of glucocorticoid treatment in sepsis are poorly understood, with consequences for the clinical guidelines for treatment. Glucocorticoids are potent anti-inflammatory mediators which exert their effects through the glucocorticoid receptor (GR). Deeper understanding about the mechanisms of GR signalling may help to guide and improve glucocorticoid treatment. The aim of this thesis was to analyse GR expression and binding capacity in experimental and human septic shock and severe inflammation with cellular specificity using flow cytometry. In the late phase of a murine sepsis model, we observed decreased GR expression in leukocytes. In a murine model of early endotoxic shock, we observed decreased GR binding capacity in spite of an increased expression, in neutrophils. Glucocorticoid treatment was beneficial only when administered early in both models. Compared to healthy subjects, GR expression was increased in leukocytes from patients during the initial sepsis phase, while GR binding capacity was only increased in lymphocytes and monocytes. In contrast, neutrophils and other leukocyte subsets displayed decreased GR binding capacity. Neutrophil numbers were increased in all patients with sepsis compared to healthy subjects. We also studied patients with burn injury after admission before any infectious event had likely occurred, and on day 7 post admission, when several of the patients had been diagnosed with sepsis. GR expression and binding capacity was increased in leukocytes on admission as compared to healthy subjects, and patients diagnosed with sepsis on day 7 had a further increased GR expression in T lymphocytes. GR binding capacity was decreased in proportion to the extent of the burn injury on day 14 post admission. In conclusion, sepsis and severe inflammation have significant impact on the expression and function of GR, likely to influence the efficiency of glucocorticoid treatment. In addition, glucocorticoid treatment is beneficial only when given early in these models of experimental sepsis.
|
|
| 6. |
- Bergquist, Maria, et al.
(författare)
-
Impairment of neutrophilic glucocorticoid receptor function in patients treated with steroids for septic shock
- 2015
-
Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 3:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glucocorticoid (GC) treatment has variable effect in sepsis. This may be explained by decreased expression or function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in patients during and after sepsis.METHODS: In this prospective, non-interventional clinical study, peripheral blood and clinical data were collected from 20 adult patients at five timepoints during sepsis and 5-13 months after recovery. GR expression and binding capacity were assessed by flow cytometry.RESULTS: GR expression was higher in T lymphocytes from patients with septic shock compared to healthy subjects (p = 0.01). While there was no difference in GR expression between GC-treated and non-treated patients, GR binding capacity was lower in GC-treated patients at admission compared to healthy subjects (p ≤ 0.03). After the acute inflammation inflammatory phase, GR binding capacity was still lower in neutrophils of GC-treated patients, compared to healthy subjects (p = 0.01). On admission, GR binding capacity in T lymphocytes and neutrophils was inversely correlated with noradrenaline dose and lactate (p ≤ 0.03).CONCLUSIONS: Our data suggest that GR expression is increased in T lymphocytes during septic shock regardless of GC treatment, while GR binding capacity is decreased in neutrophils in GC-treated patients. As neutrophils are the predominant circulating leucocyte in septic shock, their decreased GR binding capacity may impede the response to exogenous or endogenous glucocorticoids.
|
|
| 7. |
- Gudmundsson, Magni, et al.
(författare)
-
Atelectasis is inversely proportional to transpulmonary pressure during weaning from ventilator support in a large animal model
- 2018
-
Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 62:1, s. 94-104
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn mechanically ventilated, lung injured, patients without spontaneous breathing effort, atelectasis with shunt and desaturation may appear suddenly when ventilator pressures are decreased. It is not known how such a formation of atelectasis is related to transpulmonary pressure (P-L) during weaning from mechanical ventilation when the spontaneous breathing effort is increased. If the relation between P-L and atelectasis were known, monitoring of P-L might help to avoid formation of atelectasis and cyclic collapse during weaning. The main purpose of this study was to determine the relation between P-L and atelectasis in an experimental model representing weaning from mechanical ventilation. MethodsDynamic transverse computed tomography scans were acquired in ten anaesthetized, surfactant-depleted pigs with preserved spontaneous breathing, as ventilator support was lowered by sequentially reducing inspiratory pressure and positive end expiratory pressure in steps. The volumes of gas and atelectasis in the lungs were correlated with P-L obtained using oesophageal pressure recordings. Work of breathing (WOB) was assessed from Campbell diagrams. ResultsGradual decrease in P-L in both end-expiration and end-inspiration caused a proportional increase in atelectasis and decrease in the gas content (linear mixed model with an autoregressive correlation matrix; P<0.001) as the WOB increased. However, cyclic alveolar collapse during tidal ventilation did not increase significantly. ConclusionWe found a proportional correlation between atelectasis and P-L during the weaning process' in experimental mild lung injury. If confirmed in the clinical setting, a gradual tapering of ventilator support can be recommended for weaning without risk of sudden formation of atelectasis.
|
|
| 8. |
- Pellegrini, Mariangela, et al.
(författare)
-
Effects of superimposed tissue weight on regional compliance of injured lungs
- 2016
-
Ingår i: Respiratory Physiology & Neurobiology. - : Elsevier BV. - 1569-9048 .- 1878-1519. ; 228, s. 16-24
-
Tidskriftsartikel (refereegranskat)abstract
- Computed tomography (CT), together with image analysis technologies, enable the construction of regional volume (V-REG) and local transpulmonary pressure (P-TP,P-REG) maps of the lung. Purpose of this study is to assess the distribution of V-REG vs P-TP,P-REG along the gravitational axis in healthy (HL) and experimental acute lung injury conditions (eALI) at various positive end-expiratory pressures (PEEPS) and inflation volumes. Mechanically ventilated pigs underwent inspiratory hold maneuvers at increasing volumes simultaneously with lung CT scans. eALI was induced via the iv administration of oleic acid. We computed voxel-level V-REG vs P-TP,P-REG curves into eleven isogravitational planes by applying polynomial regressions. Via F-test, we determined that V-REG vs P-TP,P-REG curves derived from different anatomical planes (p-values < 1.4E-3), exposed to different PEEPs (p-values < 1.5E-5) or subtending different lung status (p-values < 3E-3) were statistically different (except for two cases of adjacent planes). Lung parenchyma exhibits different elastic behaviors based on its position and the density of superimposed tissue which can increase during lung injury.
|
|
| 9. |
|
|
| 10. |
- Pellegrini, Mariangela, et al.
(författare)
-
Expiratory Resistances Prevent Expiratory Diaphragm Contraction, Flow Limitation, and Lung Collapse
- 2020
-
Ingår i: American Journal of Respiratory and Critical Care Medicine. - : AMER THORACIC SOC. - 1073-449X .- 1535-4970. ; 3:7
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying positive end-expiratory pressure and may cause respiratory and hemodynamic complications in ventilated patients with lungs prone to collapse. During spontaneous breathing, expiratory diaphragmatic contraction counteracts tidal-EFL. We hypothesized that during both spontaneous breathing and controlled mechanical ventilation, external expiratory resistances reduce tidal-EFL.Objectives: To assess whether external expiratory resistances 1) affect expiratory diaphragmatic contraction during spontaneous breathing, 2) reduce expiratory flow and make lung compartments more homogeneous with more similar expiratory time constants, and 3) reduce tidal atelectasis, preventing hyperinflation.Methods: Three positive end-expiratory pressure levels and four external expiratory resistances were tested in 10 pigs after lung lavage. We analyzed expiratory diaphragmatic electric activity and respiratory mechanics. On the basis of computed tomography scans, four lung compartments-not inflated (atelectasis), poorly inflated, normally inflated, and hyperinflated-were defined.Measurements and Main Results: Consequently to additional external expiratory resistances, and mainly in lungs prone to collapse (at low positive end-expiratory pressure), 1) the expiratory transdiaphragmatic pressure decreased during spontaneous breathing by >10%, 2) expiratory flow was reduced and the expiratory time constants became more homogeneous, and 3) the amount of atelectasis at end-expiration decreased from 24% to 16% during spontaneous breathing and from 32% to 18% during controlled mechanical ventilation, without increasing hyperinflation.Conclusions: The expiratory modulation induced by external expiratory resistances preserves the positive effects of the expiratory brake while minimizing expiratory diaphragmatic contraction. External expiratory resistances optimize lung mechanics and limit tidal-EFL and tidal atelectasis, without increasing hyperinflation.
|
|
