Publications by authors named "Martin Silverborn"

15 Publications

  • Page 1 of 1

Impaired Differentiation of COPD Bronchial Epithelial Cells Grown on Bronchial Scaffolds.

Am J Respir Cell Mol Biol 2021 Apr 21. Epub 2021 Apr 21.

AstraZeneca, Gothenburg, Sweden;

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation, small airway remodeling and emphysema. Airway remodeling in COPD patients involves both the airway epithelium and the subepithelial extracellular matrix (ECM). However, it is currently unknown how epithelial remodeling in COPD airways depends on the relative influence from inherent defects in the epithelial cells and alterations in the ECM. To address this, we analyzed global gene expression in COPD and normal human bronchial epithelial cells (HBEC) after repopulation on decellularized bronchial scaffolds derived from COPD patients or non-COPD donors. COPD HBEC grown on bronchial scaffolds showed an impaired ability to initiate ciliated cell differentiation, which was evident on all scaffolds regardless of their origin. In addition, while normal HBEC were less affected by the disease state of the bronchial scaffolds, COPD HBEC showed a gene expression pattern indicating increased proliferation and a retained basal cell phenotype when grown on COPD compared to normal bronchial scaffolds. Mass spectrometry identified thirteen matrisome proteins as differentially abundant between COPD and normal bronchial scaffolds. These observations are consistent with COPD pathology and suggest that both epithelial cells and the ECM contribute to epithelial cell remodeling in COPD airways. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1165/rcmb.2019-0395OCDOI Listing
April 2021

Matrisome Properties of Scaffolds Direct Fibroblasts in Idiopathic Pulmonary Fibrosis.

Int J Mol Sci 2019 Aug 17;20(16). Epub 2019 Aug 17.

Lung Biology, Department of Experimental Medical Sciences, Lund University, BMC C12, Lund 221 84, Sweden.

In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression.
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http://dx.doi.org/10.3390/ijms20164013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719040PMC
August 2019

Transplantation after ex vivo lung perfusion: A midterm follow-up.

J Heart Lung Transplant 2016 11 31;35(11):1303-1310. Epub 2016 May 31.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy; Transplant Institute, Gothenburg, Sweden.

Background: A large proportion of donor lungs are discarded due to known or presumed organ dysfunction. Ex vivo lung perfusion (EVLP) has proven its value as a tool for discrimination between reversible and irreversible donor lung pathology. However, the long-term outcome after transplantation of lungs after EVLP is essentially unknown. We report short-term and midterm outcomes of recipients who received transplants of EVLP-evaluated lungs.

Methods: Single-center results of recipients of lungs with prior EVLP were compared with consecutive recipients of non-EVLP lungs (controls) during the same period. Short-term follow-up included time to extubation, time in the intensive care unit, and the presence of primary graft dysfunction at 72 hours postoperatively. Mortality and incidence of chronic lung allograft dysfunction were monitored for up to 4 years after discharge.

Results: During a 4-year period, 32 pairs of initially rejected donor lungs underwent EVLP. After EVLP, 22 double lungs and 5 single lungs were subsequently transplanted. During this period, 145 patients received transplants of conventional donor lungs that did not have EVLP and constituted the control group. Median time to extubation was 7 hours in the EVLP group and 6 hours in the non-EVLP control group (p = 0.45). Median intensive care unit stay was 4 days vs. 3 days, respectively (p = 0.15). Primary graft dysfunction grade > 1 was present in 14% in the EVLP group and in 12% in the non-EVLP group at 72 hours after transplant. Survival at 1 year was 92% in the EVLP group and 79% in the non-EVLP group. Cumulative survival and freedom from retransplantation or chronic rejection were also comparable between the 2 groups (p = 0.43) when monitored up to 4 years.

Conclusions: Selected donor lungs rejected for transplantation can be used after EVLP. This technique is effective for selection of transplantable donor lungs. Patients who received lungs evaluated under EVLP have short-term and midterm outcomes comparable to recipients of non-EVLP donor lungs.
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http://dx.doi.org/10.1016/j.healun.2016.05.021DOI Listing
November 2016

Hemofiltration in ex vivo lung perfusion-a study in experimentally induced pulmonary edema.

J Thorac Cardiovasc Surg 2016 Feb 29;151(2):570-5.e1. Epub 2015 Jun 29.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Transplant Institute, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Objectives: Ex vivo lung perfusion (EVLP) can potentially reduce pulmonary edema. In a pig model with induced pulmonary edema, we evaluated the effect of hemofiltration (HF) during EVLP on lung function, perfusate oncotic pressure, and lung weight.

Methods: In anesthetized pigs (n = 14), pulmonary edema was induced by a balloon in the left atrium, combined with crystalloid infusion (20 mL/kg), for 2 hours. The lungs were harvested, stored cold for 2 hours, and randomized to EVLP, with or without a hemofilter (HF and noHF groups, respectively, n = 7 for each). EVLP was performed with cellular perfusate at a hematocrit of 10% to 15%. Oncotic pressure, lung performance, and weight were measured before and after 180 minutes of EVLP reconditioning with or without HF.

Results: After in vivo induction of edema, arterial oxygen tension (Pao2)/inspired oxygen fraction (Fio2), and compliance decreased by 63% and 16%, respectively. Pao2/Fio2 was considerably improved at first evaluation ex vivo in both groups. HF increased oncotic pressure by 43% and decreased lung weight by 15%. The effects were negligible in the noHF group. Compliance decreased in both groups during reconditioning, although less so in the HF group (P < .05). Pao2/Fio2, shunt fraction, and oxygen saturation remained unchanged in both groups. Pulmonary flow index decreased in both groups, and was partially reversed by nitroglycerin. Dorsal atelectatic consolidations were seen in both groups.

Conclusions: In this lung-edema model, EVLP reconditioning with hyperoncotic solution did not affect the degree of lung edema. HF during EVLP increased perfusate oncotic pressure, decreased lung weight with beneficial effects on compliance, but did not improve lung oxygenation capacity.
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http://dx.doi.org/10.1016/j.jtcvs.2015.06.046DOI Listing
February 2016

Extracorporeal membrane oxygenation as a bridge to lung transplantation: a long-term study.

Eur J Cardiothorac Surg 2015 Jan 21;47(1):95-100; discussion 100. Epub 2014 Mar 21.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives: We investigated early outcomes in patients with end-stage pulmonary disease bridged with extracorporeal membrane oxygenation (ECMO) with the intention to perform lung transplantation (LTx).

Methods: ECMO was used as a bridge to LTx in 20 patients between 2005 and 2013. Most patients suffered from rapid progress of disease and most failed to stabilize on mechanical ventilation. Sixteen patients (10 males, median age 42 years, range 25-59) underwent LTx after ECMO support for a median of 9 (range 1-229) days. Most patients were not on the waiting list while receiving ECMO, but after being assessed were on the waiting list for a median of 6 (range 1-72) days before LTx or death occurred. Median follow-up at 535 (range 36-3074) days was 100% complete, 9 patients have been followed for >1 year and 4 patients have been bridged during 2013.

Results: Four patients died on ECMO waiting for a donor and as intention-to-treat, the success for bridging was 80% (16/20) and 1-year survival was 62% (10/16, not including 4 with <1-year follow-up). For those who underwent LTx, 3 patients died in-hospital after LTx on Days 0, 16 and 82, respectively, and currently, 11/16 (69%) are alive and 1-year survival for transplanted patients was 9/12 (75%). Median ICU stay before and after LTx was 9 (range 2-229) days and 20 (range 0-53) days, respectively. At follow-up, lung function was evaluated, and mean forced expiratory volume at 1 s and forced vital capacity were 56±22% of predicted and 74±24% of predicted, respectively.

Conclusions: ECMO used as a bridge to LTx results in acceptable survival in selected patients with end-stage pulmonary disease.
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http://dx.doi.org/10.1093/ejcts/ezu112DOI Listing
January 2015

Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study.

Eur J Cardiothorac Surg 2014 Jan 10;45(1):40-4; discussion 44-5. Epub 2013 May 10.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objectives: An increasing number of studies have shown that ex vivo lung perfusion (EVLP) is safe and that rejected donor lungs can be resuscitated and used for lung transplantation (LTx). Early clinical outcomes in patients transplanted with reconditioned lungs at our centre were reviewed and compared with those of contemporary non-EVLP controls.

Methods: During 18 months starting January 2011, 11 pairs of donor lungs initially deemed unsuitable for transplantation underwent EVLP. Haemodynamic (pulmonary flow, vascular resistance and artery pressure) and respiratory (peak airway pressure and compliance) parameters were analysed during evaluation. Lungs that improved (n = 11) to meet International Society of Heart and Lung Transplantation criteria were transplanted and compared with patients transplanted with non-EVLP lungs (n = 47) during the same time period.

Results: Donor lungs were initially rejected due to either inferior PaO2/FiO2 ratio (n = 9), bilateral infiltrate on chest X-ray (n = 1) or ongoing extra corporeal membrane oxygenation (n = 1). The donor lungs improved from a mean PaO2/FiO2 ratio of 27.9 kPa in the donor to a mean of 59.6 kPa at the end of the EVLP (median improvement 28.4 kPa, range 21.0-50.7 kPa). Two single lungs were deemed unsuitable and not used for LTx. Eleven recipients from the regular waiting list underwent either single (n = 3) LTx or double (n = 8) LTx with EVLP-treated lungs. The median time to extubation (12 (range, 3-912) vs 6 (range, 2-1296) h) and median intensive care unit (ICU) stay (152 (range, 40-625) vs 48 (range, 22-1632) h) were longer in the EVLP group (P = 0.05 and P = 0.01, respectively). There were no differences in length of hospital stay (median 28 (range 25-93) vs 28 (18-209), P = 0.21). Two patients in the EVLP group and 6 in the control group had primary graft dysfunction >Grade 1 at 72 h postoperatively. Three patients in the control group died before discharge. All recipients of EVLP lungs were discharged alive from hospital.

Conclusions: The use of EVLP seems safe and indicates that lungs otherwise refused for LTx can be recovered and subsequently used for transplantation, although time to extubation and ICU stay were longer for the EVLP group.
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http://dx.doi.org/10.1093/ejcts/ezt250DOI Listing
January 2014

Transplantation of initially rejected donor lungs after ex vivo lung perfusion.

J Thorac Cardiovasc Surg 2012 Nov 17;144(5):1222-8. Epub 2012 Sep 17.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objective: Ex vivo lung perfusion has the potential to increase the number of patients treated with lung transplantation. Our initial clinical experience with ex vivo lung perfusion is reviewed as well as early clinical outcome in patients transplanted with reconditioned lungs.

Methods: Six pairs of donor lungs deemed unsuitable for transplantation underwent ex vivo lung perfusion with Steen solution mixed with red blood cells to a hematocrit of 10% to 15%. After reconditioning, lung function was evaluated and acceptable lungs were transplanted. Technical experience with ex vivo lung perfusion as well as clinical outcome for patients transplanted with ex vivo lung perfusion-treated lungs were evaluated.

Results: Donor lungs initially rejected either as a result of an inferior partial pressure of arterial oxygen/ fraction of inspired oxygen (n = 5; mean, 20.5 kPa; range, 9.1-29.9 kPa) or infiltrate on chest radiograph (n = 1) improved their oxygenation capacity to a mean partial pressure of arterial oxygen/fraction of inspired oxygen of 57 ± 10 kPa during the ex vivo lung perfusion (mean improvement, 33.6 kPa; range, 21-51 kPa; P < .01). During evaluation, hemodynamic (flow, vascular resistance, pressure) and respiratory (peak airway pressure, compliance) parameters were stable. Two single lungs were not used for lung transplantation because of subpleural hematoma or edema. Six recipients from the regular waiting list underwent single (n = 2) or double (n = 4) lung transplantation. One patient had primary graft dysfunction grade 2 at 72 hours. Median time to extubation was 7 hours. All patients survived 30 days and were discharged in good condition from the hospital.

Conclusions: The use of ex vivo lung perfusion seems safe and indicates that some lungs otherwise refused for lung transplantation can be recovered and transplanted with acceptable short-term results.
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http://dx.doi.org/10.1016/j.jtcvs.2012.08.011DOI Listing
November 2012

[ECMO can be a bridge to lung transplantation. New method saves life in acute pulmonary failure according to a retrospective study].

Lakartidningen 2011 Aug 10-23;108(32-33):1493-7

Transplantationscentrum, Sahlgrenska akademin och Sahlgrenska universitetssjukhuset, Göteborg.

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September 2011

Usefulness of extracorporeal membrane oxygenation as a bridge to lung transplantation: a descriptive study.

J Heart Lung Transplant 2011 Jan 8;30(1):103-7. Epub 2010 Oct 8.

Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland.

Background: This retrospective study investigated early outcome in patients with end-stage pulmonary disease bridged with extracorporeal membrane oxygenation (ECMO) with the intention of lung transplantation (LTx) in 2 Scandinavian transplant centers.

Methods: ECMO was used as a bridge to LTx in 16 patients between 2005 and 2009 at Sahlgrenska and Helsinki University Hospitals. Most patients were late referrals for LTx, and all failed to stabilize on mechanical ventilation. Thirteen patients (7 men) who were a mean age of 41 ± 8 years (range, 25-51 years) underwent LTx after a mean ECMO support of 17 days (range, 1-59 days). Mean follow-up at 25 ± 19 months was 100% complete.

Results: Three patients died on ECMO while waiting for a donor, and 1 patient died 82 days after LTx; thus, by intention-to-treat, the success for bridging is 81% and 1-year survival is 75%. All other patients survived, and 1-year survival for transplant recipients was 92% ± 7%. Mean intensive care unit stay after LTx was 28 ± 18 days (range, 3-53 days). All patients were doing well at follow-up; however, 2 patients underwent retransplantation due to bronchiolitis obliterans syndrome at 13 and 21 months after the initial ECMO bridge to LTx procedure. Lung function was evaluated at follow-up, and mean forced expiratory volume in 1 second was 2.0 ± 0.7 l (62% ± 23% of predicted) and forced vital capacity was 3.1 ± 0.6 l (74% ± 21% of predicted).

Conclusion: ECMO used as a bridge to LTx results in excellent short-term survival in selected patients with end-stage pulmonary disease.
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http://dx.doi.org/10.1016/j.healun.2010.08.017DOI Listing
January 2011

Lung transplantation in patients with cystic fibrosis and Mycobacterium abscessus infection.

J Cyst Fibros 2010 Jul 18;9(4):272-6. Epub 2010 Apr 18.

Department of Respiratory Medicine and Allergology, Bruna Stråket 11b, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.

Mycobacterium abscessus lung disease is difficult to treat and has been considered a strong relative contraindication to lung transplantation. We performed double lung transplantation in three cystic fibrosis patients with ongoing, and a fourth with recent treatment for Mycobacterium abscessus lung infection. Despite prolonged antibiotic courses and adjustment of immunosuppressive therapy the first three patients developed skin infection and abscesses. At follow-up after 1, 3, 5 and 7years respectively no patient had evidence of M abscessus infection and all had stable lung function. Lung transplantation in patients with M abscessus lung infection is feasible but may involve severe complications.
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http://dx.doi.org/10.1016/j.jcf.2010.03.008DOI Listing
July 2010

Vascular resistance and endothelial function in cyclosporine-treated lung transplant recipients.

Transpl Int 2006 Dec;19(12):974-81

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

The majority of patients undergoing solid organ transplantation develop hypertension, to which vasoconstriction and impaired endothelial function have been suggested to contribute. We compared basal vascular resistance and nitric oxide-mediated endothelial-dependent and independent vasoreactivity between cyclosporine-treated lung transplant recipients and healthy subjects. Forearm blood flow was measured by venous occlusion plethysmography at rest and during acetylcholine, glyceryltrinitrate and N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion in 11 lung transplant recipients 3-5 years after transplantation and in eight healthy subjects. Forearm vascular resistance (FVR) was calculated. Plasma levels of endothelin-1 (ET-1) and von Willebrand factor (vWf) were analysed. Basal vascular resistance was 40% lower in transplant recipients than in healthy subjects (P = 0.021). Endothelial-dependent and independent vasodilation did not differ. Plasma levels of ET-1 and vWf were higher in transplant recipients (P = 0.009 and P < 0.001 respectively). There was a significant correlation between ET-1 levels and FVR in healthy subjects (r = 0.83, P = 0.042), but not in transplant recipients (r = -0.14, P = 0.70). The findings oppose the theory of generalized vasoconstriction and impaired endothelial function in the pathogenesis of hypertension after transplantation. Increased plasma levels of ET-1 do not cause increased FVR in lung transplant recipients.
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http://dx.doi.org/10.1111/j.1432-2277.2006.00372.xDOI Listing
December 2006

Ex vivo evaluation of nonacceptable donor lungs.

Ann Thorac Surg 2006 Feb;81(2):460-6

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Only a minority of the potential candidates for lung donation are considered suitable, using current evaluation methods. A new method for ex vivo evaluation, with the potential for reconditioning of marginal and nonacceptable lungs, has been developed. This is a report of the ex vivo evaluation of six donor lungs deemed nonacceptable (arterial oxygen pressure less than 40 kPa) by the Scandiatransplant, Eurotransplant, and UK transplant organizations.

Methods: The lungs are perfused ex vivo with Steen solution, a lung evaluation-preservation solution, mixed with red blood cells to a hematocrit of 15%. This extracellular solution is designed to have an optimal colloid osmotic pressure so that physiologic pressure and flow can be maintained without development of pulmonary edema. An oxygenator connected to the extracorporeal circuit maintains a normal mixed venous blood gas level in the perfusate. The lungs are ventilated and evaluated through analyses of pulmonary vascular resistance, oxygenation capacity, and arterial carbon dioxide pressure minus end-tidal carbon dioxide difference.

Results: The arterial oxygen pressure (inspired oxygen fraction, 1.0) increased from 27 kPa (range, 17 to 34 kPa) in situ in the organ donor at the referring hospital to 57 kPa (range, 39 to 66 kPa) during the ex vivo evaluation. The pulmonary vascular resistance varied from 3.2 to 5.7 Wood units, and the arterial carbon dioxide pressure minus end-tidal carbon dioxide difference was in the range of 1 to 2.5 kPa.

Conclusions: The arterial oxygen pressure improves significantly in this model. This ex vivo evaluation model is a valuable addition to the armamentarium in finding acceptable lungs in a donor population with inferior arterial oxygen pressure values.
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http://dx.doi.org/10.1016/j.athoracsur.2005.08.015DOI Listing
February 2006

New-onset cardiovascular risk factors in lung transplant recipients.

J Heart Lung Transplant 2005 Oct;24(10):1536-43

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Cardiovascular disease (CVD) is a common cause of morbidity and mortality after solid-organ transplantation. Both pre-existing cardiovascular risk factors in recipients and immunosuppressive drug toxicity may contribute to CVD. We sought to describe the prevalence of new-onset hypertension, hypercholesterolemia and diabetes mellitus in lung transplant recipients and to identify predisposing factors.

Methods: One hundred twenty-six patients without pre-transplant hypertension, hypercholesterolemia or diabetes were included in a retrospective descriptive study. All patients were initially on cyclosporine-based triple immunosuppression. Cumulative prevalence of new-onset hypertension, hypercholesterolemia and diabetes were calculated. A multivariate Cox regression model was used to identify independent pre-operative predictors.

Results: By 3 years after transplantation, 90% of patients had developed at least 1 cardiovascular risk factor and 40% developed > or = 2 risk factors. The cumulative prevalence of new-onset hypertension at 1, 3, 5 and 7 years was 45%, 65%, 67% and 72%, respectively. The corresponding prevalence for hypercholesterolemia was 16%, 33%, 48% and 58%, and for diabetes 6%, 7%, 7% and 10%, respectively. The independent pre-transplant predictors were: for hypertension, diastolic blood pressure (odds ratio: 2.1 per 10 mm Hg [95% confidence interval: 1.3 to 3.5], p = 0.005); for hypercholesterolemia, serum cholesterol level (OR: 1.8 per mmol/liter [95% CI: 1.3 to 2.5], p < 0.001); and, for diabetes, cystic fibrosis diagnosis (OR: 7.4 [95% CI: 1.6 to 35.6], p = 0.01) and blood glucose level (OR 2.2 per mmol/liter [95% CI 1.1 to 4.5], p = 0.02).

Conclusions: The majority of cyclosporine-treated lung transplant recipients develop new-onset hypertension or hypercholesterolemia early after transplantation. Pre-transplant blood pressure, serum cholesterol levels and blood glucose levels are independent predictors of post-transplant hypertension, hypercholesterolemia and diabetes, respectively.
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http://dx.doi.org/10.1016/j.healun.2005.01.004DOI Listing
October 2005

Blunted vascular response to endothelin-a receptor blockade in cyclosporine-treated lung transplant recipients.

J Heart Lung Transplant 2005 Jun;24(6):665-70

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade.

Methods: The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed.

Results: Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups).

Conclusions: The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.
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http://dx.doi.org/10.1016/j.healun.2004.04.010DOI Listing
June 2005

Increased arterial stiffness in cyclosporine-treated lung transplant recipients early after transplantation.

Clin Transplant 2004 Aug;18(4):473-9

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: The majority of patients undergoing solid organ transplantation develop hypertension, to which cyclosporine (CsA)-induced peripheral vasoconstriction may contribute. We hypothesized that CsA-treated transplant recipients have an increased basal vascular tone and an altered response to nitric oxide. To test this hypothesis arterial resistance, non-endothelial dependent relaxation and arterial stiffness were investigated in CsA-treated lung transplant recipients within 18 months after transplantation.

Methods: In study 1, forearm blood flow (FBF) was measured by venous occlusion plethysmography at baseline and during glyceryl trinitrate (GTN) and N(G)-monomethyl-l-arginine acetate (l-NMMA) infusion in seven lung transplant recipients and nine healthy subjects. In study 2, arterial stiffness in carotid (CCA) and radial artery (RA) was measured by ultrasound (echo-tracking) in 10 lung transplant recipients, 12 healthy subjects and six patients waiting for lung transplantation.

Results: Basal FBF (3.1 +/- 0.2 vs. 3.0 +/- 0.3 mL/min, p = 0.79) and forearm arterial resistance (36 +/- 3 vs. 33 +/- 3 mmHg/mL/min, p = 0.60) did not differ between transplant recipients and controls. GTN infusion increased and l-NMMA decreased blood flow equally in both groups. Transplant recipients had increased arterial stiffness compared to both pre-transplant patients and healthy subjects (CCA stiffness index 11.7 +/- 1.1 vs. 8.5 +/- 0.2 and 8.6 +/- 0.6, p < 0.05 both; RA stiffness index 14.7 +/- 1.5 vs. 8.9 +/- 1.3 and 10.6 +/- 0.7, p < 0.05 both).

Conclusions: Forearm blood flow and arterial resistance did not differ between healthy subjects and cyclosporine-treated lung transplant recipients early after transplantation. Increased arterial stiffness was demonstrated in transplant recipients, which may have implications for future development of transplant hypertension.
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http://dx.doi.org/10.1111/j.1399-0012.2004.00193.xDOI Listing
August 2004