| 1. |
- dos Santos, Claudia C., et al.
(författare)
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Network Analysis of Transcriptional Responses Induced by Mesenchymal Stem Cell Treatment of Experimental Sepsis
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:5, s. 1681-1692
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Tidskriftsartikel (refereegranskat)abstract
- Although bone marrow derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57B1/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P <= 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response. (Am J Pathol 2012, 181:1681-1692; http://dx.doi.org/10.1016/j.ajpath.2012.08.009)
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| 2. |
- Larsson, Marcus, et al.
(författare)
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Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin--a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy.
- 2003
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961. ; 23:4, s. 199-203
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Tidskriftsartikel (refereegranskat)abstract
- Cryo-transmission electron microscopy (cryo-TEM) is a rather artefact-free method, well suited to study the alveolar surfactant system. A pharmacy grade porcine lung surfactant extract (HL-10) was mixed with human SP-A and Ringer's solution (for calcium ions), and it was shown by cryo-TEM that the tubular myelin (TM) type of structure was reconstituted. These aggregates were associated to liposomal aggregates, and resulted in macroscopic phase-separation. This phase showed a weak birefringence in the polarising microscope, which is characteristic for a liquid-crystalline type of structure. TM from rabbit lung lavage was also examined, and showed the same periodic arrangement of bilayers as alveolar surface layer from freshly cut rabbit lungs deposited directly on the cryo-TEM grids. The distance between the bilayers of TM was 40-50 nm, and an electron dense material, assumed to be SP-A, was sometimes seen to occur periodically along the bilayers, oriented perpendicularly to the tubuli. The results are consistent with the surface-phase model of the alveolar lining.
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| 3. |
- Larsson, Marcus, et al.
(författare)
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Enhanced efficacy of porcine lung surfactant extract by utilization of its aqueous swelling dynamics.
- 2002
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961. ; 22:1, s. 39-48
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Tidskriftsartikel (refereegranskat)abstract
- This study investigates the interactions between a porcine lung surfactant (PLS) extract and distilled water, saline solution or Ringer solution. The phases which coexist in equilibrium with water or electrolyte solutions were analysed by X-ray diffraction and cryo transmission electron microscopy (cryo-TEM). A lamellar phase with a structure unit consisting of double bilayers was observed in water, whereas lamellar phases with the usual bilayer structure unit were formed in saline and in Ringer solutions. At 25 degrees C the presence of a 4.2-A peak in the X-ray diffraction wide-angle region of these three maximally swollen phases showed that most of the hydrocarbon chains were organized in a crystalline packing. At 42 degrees C the chains in all three phases were melted which, in combination with the low-angle diffraction, shows that they were liquid-crystalline. Polyhedral-like vesicles and spherically shaped multilamellar vesicles were observed in cryo-TEM. The bilayer unit structures were consistent with the periodicity seen by X-ray diffraction. The dynamic swelling behaviour was followed in the polarizing microscope. A remarkable growth of birefringent networks was seen at the air interface of samples swollen in Ringer solution and saline solution. No such interfacial growth phenomena were observed during swelling in water without electrolytes. Then, these dynamics were analysed in relation to time-dependent pulmonary administration of the surfactant extract in rats. Variation in the time of administration (20 and 60 min) after mixing the extract with saline or Ringer solution showed clear differences in physiological effects. At pulmonary administration when the swelling behaviour in vitro showed a maximum in dynamics, the arterial oxygenation was superior to that of administration at a time after a steady-state had been reached. This means that the clinical performance of mammalian lung surfactant extracts can be significantly improved by taking the time-dependent aqueous swelling of the extract into account.
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| 4. |
- Shan, Yuexin, et al.
(författare)
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ATF3 Protects Pulmonary Resident Cells from Acute and Ventilator-Induced Lung Injury by Preventing Nrf2 Degradation
- 2015
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Ingår i: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 22:8, s. 651-668
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Ventilator-induced lung injury (VILI) contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). Absence of activating transcription factor 3 (ATF3) confers susceptibility to ALI/VILI. To identify cell-specific ATF3-dependent mechanisms of susceptibility to ALI/VILI, we generated ATF3 chimera by adoptive bone marrow (BM) transfer and randomized to inhaled saline or lipopolysacharide (LPS) in the presence of mechanical ventilation (MV). Adenovirus vectors to silence or overexpress ATF3 were used in primary human bronchial epithelial cells and murine BM-derived macrophages from wild-type or ATF3-deficient mice. Results: Absence of ATF3 in myeloid-derived cells caused increased pulmonary cellular infiltration. In contrast, absence of ATF3 in parenchymal cells resulted in loss of alveolar-capillary membrane integrity and increased exudative edema. ATF3-deficient macrophages were unable to limit the expression of pro-inflammatory mediators. Knockdown of ATF3 in resident cells resulted in decreased junctional protein expression and increased paracellular leak. ATF3 overexpression abrogated LPS induced membrane permeability. Despite release of ATF3-dependent Nrf2 transcriptional inhibition, mice that lacked ATF3 expression in resident cells had increased Nrf2 protein degradation. Innovation: In our model, in the absence of ATF3 in parenchymal cells increased Nrf2 degradation is the result of increased Keap-1 expression and loss of DJ-1 (Parkinson disease [autosomal recessive, early onset] 7), previously not known to play a role in lung injury. Conclusion: Results suggest that ATF3 confers protection to lung injury by preventing inflammatory cell recruitment and barrier disruption in a cell-specific manner, opening novel opportunities for cell specific therapy for ALI/VILI. Antioxid. Redox Signal. 22, 651-668.
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