[Show abstract][Hide abstract] ABSTRACT: ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) alpha1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD. METHODS: Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and "normal" MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR. RESULTS: A total of 162 genes were found to be differentially expressed (p-value [less than or equal to] 0.05 and |FC| [greater than or equal to] 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Kruppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy. CONCLUSIONS: These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.
[Show abstract][Hide abstract] ABSTRACT: Recent studies have revealed that microRNAs (miRNAs) play a key role in the control of angiogenesis and vascular remodeling. Specific miRNAs in plexiform vasculopathy of severe pulmonary arterial hypertension (PAH) in humans have not yet been investigated.
We analyzed expression of miR-143/145 (vascular smooth muscle-specific), miR-126 (endothelial-specific) and related mRNAs in plexiform (PLs) and concentric lesions (CLs), which had been laser-microdissected from specimens of formalin-fixed, paraffin-embedded, explanted lungs of PAH patients (n = 12) and unaffected controls (n = 8). Samples were analyzed by real-time polymerase chain reaction, and protein expression was determined by immunohistochemistry.
Expression levels of miR-143/145 and its target proteins (e.g., myocardin, smooth muscle myosin heavy chain) were found to be significantly higher in CLs than in PLs, whereas miR-126 and VEGF-A were significantly up-regulated in PLs when compared with CLs, indicating a more prominent angiogenic phenotype of PL. This correlates with a down-regulation of miR-204 as well as an up-regulation of miR-21 in PLs, which in turn corresponds to enhanced cell proliferation.
Our findings show that morphologic changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 04/2012; 31(7):764-72. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background In adults, human papillomaviruses (HPV), lichen sclerosus et atrophicus (LSA) and phimosis are considered to be major risk factors for penile cancer. In boys, a possible association between phimosis, LSA and HPV has been suggested. Objective To investigate the role of HPV in the persistence of phimosis in children. Patients and methods Out of a cohort of 420 boys presenting with foreskin problems, we prospectively sampled the preputial tissue of 82 patients during circumcision: 46 with steroid-naïve and 36 with steroid-resistant phimosis. All foreskins were assessed clinically and histopathologically with regard to appearance, inflammation, oedema, epithelial degeneration and fibrosis. The viral status of the foreskins was determined by immunohistochemistry and highly sensitive PCR, with subsequent subtyping by DNA hybridization (HPV types 6, 11, 16, 18, 31, 33, 35, 39, 42, 44, 45, 51-54, 56, 58, 59, 61, 62, 66-68, 70, 72, 73, 81-84, 90, 91). Results The foreskins appeared normal in 62 boys and suggestive of LSA in one single case. Small cracks or white scars were present in seven steroid-naïve and 12 steroid-resistant foreskins. LSA was diagnosed microscopically in two of the steroid-naïve and six of the steroid-pretreated group. No evidence of HPV was found in any of the juvenile foreskins. Conclusions Our prospective study has provided evidence that HPV is not usually present in the foreskin of boys with persistent phimosis after their first year of life and that topical glucocorticoid treatment failure is not associated with HPV or any specific histopathological changes.
Journal of the European Academy of Dermatology and Venereology 04/2012; · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV)-associated posttransplant smooth muscle tumors (PTSMT) are very rare complications. We aimed to provide a clinicopathological characterization which is based on our own case series (n = 5) as well as previously reported PTSMT cases (n = 63). Meta-analysis of PTSMT and molecular analysis of tumor cells from our cohort was performed. Most PTSMT developed in kidney-transplanted patients (n = 41/68, 60%). Liver/transplant liver was the main site of manifestation (n = 38/68, 56%). Tumors occurred after a median interval of 48 months (range 5-348) and developed earlier in children than in adults. Most tumors showed no marked cellular atypia, low mitosis rate and no tumor necrosis. Gene expression analysis of 20 EBV-related genes, including two microRNAs, revealed overexpression of MYC (p = 0.0357). Therapy was mainly based on surgical resection or reduced immunosuppression but no significant differences in overall survival were evident. Lower overall survival was associated with multiorgan involvement (n = 33/68, 48.5%) and particularly with intracranial PTSMT manifestation (n = 7/68, 10%; p < 0.02), but not transplant involvement (n = 11/68, 16%). In summary, PTSMT differ from conventional leiomyosarcomas by their lack of marked atypia, unusual sites of involvement and defining EBV association. Surgery and reduced immunosuppression show comparable clinical results and prognosis is associated with intracranial manifestation.
American Journal of Transplantation 03/2012; 12(7):1908-17. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three-dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling-associated genes, such as HIF1a, TGF-β1, VEGF-α, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy.
American Journal Of Pathology 07/2011; 179(1):167-79. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).
GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.
GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.
GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.
Respiratory research 05/2011; 12:62. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Die Lungentransplantation ist eine ultimative Therapie bei fortgeschrittenen kongenitalen und erworbenen Lungenerkrankungen
bei Kindern und Erwachsenen. Das Langzeitüberleben lungentransplantierter Patienten zeigt im Gegensatz zur Überlebensrate
innerhalb des ersten Jahres in der Vergangenheit kaum Verbesserung. Neben anderen Faktoren ist die akute zelluläre Abstoßung
für die verminderte Transplantatfunktion ursächlich und kann zu chronischer Abstoßung (Bronchiolitis-obliterans-Syndrom, BOS)
führen. Die histomorphologische Beurteilung transbronchial gewonnener Lungenparenchymbiopsien ist nach wie vor die verlässlichste
Methode zur Diagnose einer Lungentransplantatabstoßung. 2006 hat die „International Society for Heart and Lung Transplantation“
(ISHLT) ein revidiertes und vereinfachtes Graduierungsschema für Lungentransplantatabstoßung vorgelegt.
Lung transplantation is the ultimate therapeutical approach for the treatment of both children and adults with terminal congenital
or acquired lung disease. In contrast to survival rates during the first year following transplantation, the long-term survival
for patients after lung transplantation has not significantly improved in the past. In addition to other complications, acute
cellular rejection constitutes a major cause for diminished function of pulmonary grafts, and can, among other factors, be
causative for chronic rejection (bronchiolitis obliterans syndrome, BOS). In 2006, the International Society for Heart and
Lung Transplantation (ISHLT) provided a revised version of the grading system for acute and chronic rejection of pulmonary
SchlüsselwörterLungentransplantation–Akute zelluläre Abstoßung–Bronchiolitis-obliterans-Syndrom–Histomorphologie–Lungenbiopsie
KeywordsLung transplantation–Acute cellular rejection–Bronchiolitis obliterans syndrome–Histopathology–Lung biopsy
Der Pathologe 03/2011; 32(2):104-112. · 0.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung transplantation is the ultimate therapeutical approach for the treatment of both children and adults with terminal congenital or acquired lung disease. In contrast to survival rates during the first year following transplantation, the long-term survival for patients after lung transplantation has not significantly improved in the past. In addition to other complications, acute cellular rejection constitutes a major cause for diminished function of pulmonary grafts, and can, among other factors, be causative for chronic rejection (bronchiolitis obliterans syndrome, BOS). In 2006, the International Society for Heart and Lung Transplantation (ISHLT) provided a revised version of the grading system for acute and chronic rejection of pulmonary grafts.
Der Pathologe 03/2011; 32(2):104-12. · 0.64 Impact Factor