The Site and Nature of Airway Obstruction after Lung Transplantation

Verleden, Stijn E.; Vasilescu, Dragoş M.; Willems, Stijn; Ruttens, David; Vos, Robin; Vandermeulen, Elly; Hostens, Jeroen; McDonough, John E.; Verbeken, Erik; Verschakelen, Johny; Raemdonck, Dirk Van; Rondelet, Benoît; Knoop, Christiane; Decramer, Marc; Cooper, Joel D.; Hogg, James C.; Verleden, Geert M.; Vanaudenaerde, Bart M.

doi:10.1164/rccm.201310-1894oc

Cited by 85 publications

(76 citation statements)

References 22 publications

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“…An earlier report from our laboratories analysed explanted lungs of patients with the BOS clinical phenotype of CLAD [13] and showed no difference in the total number of visible airways and terminal bronchioles between BOS and control lungs. However, a reduction in the lumens of the smaller bronchi and pre-terminal bronchioles by a constrictive process could be observed.…”

Section: Introductionmentioning

confidence: 79%

“…The protocol for processing and sampling the lung specimens has been described in detail elsewhere [13,15]. Briefly, each lung was inflated with air to a transpulmonary pressure of 30 cmH 2 O, and then deflated to 10 cmH 2 O and held in that position while they were frozen solid in liquid nitrogen vapour and stored at −80°C.…”

Section: Specimen Processingmentioning

confidence: 99%

“…When convenient, an MDCT scan of the frozen specimen was obtained using a Siemens Somatom definition flash (120 kV, 110 mAs, reconstructed at 0.6 mm in plane resolution, and a slice thickness of 1 mm, kernel B60 sharp). This MDCT scan was used to calculate lung mass, volume and density as previously described [13]. The airway branches were counted starting from the main stem bronchus (generation 1), and reported as the number of airway bifurcations per generation.…”

Section: Specimen Processingmentioning

confidence: 99%

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Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

et al. 2015

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Chronic lung allograft dysfunction (CLAD) remains the major barrier to long-term success after lung transplantation. This report compares gross and microscopic features of lungs removed from patients receiving a redo-transplant as treatment for CLAD.Lungs donated by patients with either the bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) phenotype of CLAD and appropriate control lungs (eight per group) were airinflated, frozen solid and kept frozen while a multi-detector computed tomography (MDCT) was obtained. The lung was then cut into 2-cm thick transverse slices and sampled for micro-CT and histopathology.The MDCT showed reduced lung volume with increased lung weight and density in RAS versus BOS and control ( p<0.05). Although pre-terminal bronchioles were obstructed in both phenotypes, RAS lungs showed a reduction of pre-terminal bronchioles ( p<0.01). Micro-CT and matched histopathology showed that RAS was associated with reduced numbers of terminal bronchioles/lung compared to BOS and controls ( p<0.01), with expansion of the interstitial compartment and obliteration of the alveolar airspaces by fibrous connective tissue.RAS is associated with greater destruction of both pre-terminal and terminal bronchioles. Additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue. @ERSpublications Restrictive allograft syndrome is associated with greater destruction of both pre-terminal and terminal bronchioles

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Section: Introductionmentioning

confidence: 79%

Section: Specimen Processingmentioning

confidence: 99%

Section: Specimen Processingmentioning

confidence: 99%

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Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

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“…The introduction of azithromycin changed the field and allowed to differentiate BOS in a neutrophilic phenotype, which may be responsive to azithromycin treatment, and a non-neutrophilic phenotype that is very difficult to treat and usually does not respond to azithromycin. This last phenotype is indeed characterized by fibrotic plugging of the preterminal bronchioles, but in addition shows limited areas of complete collapse of airways, without any overt intraluminal fibrosis nor inflammation being present [20]. As a consequence, it seems acceptable that treatment of inflammation does not improve the pulmonary function in all patients.…”

Section: Expert Opinionmentioning

confidence: 99%

Are we near to an effective drug treatment for bronchiolitis obliterans?

Verleden

Vos

Dupont

et al. 2014

Expert Opinion on Pharmacotherapy

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“…a reduced synthesis of matrix proteins upon IL-1α activation, challenges this view of IL-1α as a profibrotic mediator. Thus, whether IL-1α is involved in the loss of small conducting airways or in peribronchial fibrosis observed in COPD [21] remains unclear. In cancer, BAE et al [22] showed that IL-1α may enhance oral squamous carcinoma-associated fibroblast proliferation through the secretion of CCL7, CXCL1 and IL-8/CXCL8 chemokines.…”

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Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

2016

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@ERSpublicationsInterleukin-1 alpha released by airway epithelial cells may instruct fibroblasts to become proinflammatory in COPD http://ow.ly/CLYK301tyOjThe lungs are continuously exposed to inhaled particles and irritants. Tobacco smoking is the leading cause of several airway diseases, including lung cancer, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In COPD, repeated exposure to cigarette smoke induces chronic inflammation and structural remodelling of the airways, with peribronchial fibrosis and epithelial-to-mesenchymal transition [1], resulting in (mostly irreversible) airway obstruction. Thus, abnormal airway responses to noxious gases probably results from aberrant signalling and crosstalk between epithelial, mesenchymal and immune cells.In this issue of the European Respiratory Journal, OSEI et al.[2] describe how epithelial cells signal to fibroblasts through interleukin (IL)-1α, with relevance to COPD. Using co-cultures of human primary cells (bronchial epithelial cells (BECs) and lung fibroblasts) and human cell lines (MRC5 fetal fibroblasts and 16HBE epithelial cells), the authors show that co-culture of BECs and fibroblasts induced the production of heat shock protein (Hsp)70, IL-8/CXCL8 and IL-1β by lung fibroblasts, while decreasing expression of α-smooth muscle actin, transforming growth factor (TGF)-β1 and extracellular matrix proteins. These effects, which were not different between control-and COPD-derived cells, were recapitulated by using BEC (16HBE)-conditioned medium, suggesting the requirement for soluble factor(s). Using neutralising antibodies, the authors went on to demonstrate that release of CXCL8 and Hsp70 by fibroblasts in the co-culture system was independent of IL-1β and prostaglandin E2 but dependent on IL-1α. In addition, IL-1α release by BECs was enhanced in COPD-derived cells by exposure to cigarette smoke extract. Although this in vitro model may not completely recapitulate the in vivo situation, it provides important new insights regarding the signals delivered by airway epithelial cells and regulating mesenchymal cells.There is accumulating evidence that BECs are key cells in frontline defence that directly signal to immune cells, in particular antigen-presenting cells [3,4]. Several previous works identified that BECs shape the immune response engaged by pathogens [5]. For instance, BECs exposed to Klebsiella pneumoniae regulate local immune responses notably by acting on the myeloid dendritic cell network [6]. Respiratory syncytial virus-infected BECs regulate CD8 + T-cell activation and antiviral activity, according to changes in epithelial expression of the "checkpoint" immune receptor PD-L1 [7]. BECs also regulate dendritic cell differentiation and maturation as well as responsiveness to lipopolysaccharide [8], and inhibit T-cell recall responses towards common aeroallergens in order to ensure mucosal homeostasis and dampen allergic responses [9]. It has also been shown in asthma that BECs may suppress constitutive and IgE-depen...

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The Site and Nature of Airway Obstruction after Lung Transplantation

Abstract: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

Cited by 85 publications

References 22 publications

Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

Are we near to an effective drug treatment for bronchiolitis obliterans?

Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

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