Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Ghobadi, Ghazaleh; Bartelds, Beatrijs; Veen, van der Sonja; Dickinson, Michael G.; Brandenburg, S.; Berger, Rudolphus; Langendijk, Johannes A.; Coppes, Robert P.; Luijk, van

doi:10.1136/thoraxjnl-2011-200346

Cited by 66 publications

(58 citation statements)

References 61 publications

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“…42 In 1 case, lung irradiation in rats resulted in disruption of the endothelium in the pulmonary vasculature, followed by vascular remodeling and PAH. 43 Interestingly, this effect was not seen in mice receiving control BM cells. The pulmonary vasculature is the first capillary bed that the CD133 ϩ cells encounter after IV injection.…”

Section: Discussionmentioning

confidence: 98%

Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

Asosingh

Farha

Lichtin

et al. 2012

Blood

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Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived IntroductionVascular endothelial injury with in situ thrombi is a typical pathologic finding in pulmonary arterial hypertension (PAH). Progressive disease is characterized by complex vascular malformations composed of disorganized proliferating monoclonal endothelial cells with neointima formation. 1 Although endothelial injury is hypothesized to account for the origins of PAH, the underlying mechanism of the vascular injury is unknown. Hematopoietic myeloid proangiogenic progenitors play a central role in endothelial injury and repair. We and others have reported that distinct 2-4 or indolent 5 myeloid abnormalities are present in the BM of the majority, if not all, of patients with PAH and even in unaffected family members 5 in familial cases of the disease. These findings and the unexplained high incidence of PAH among patients with myeloproliferative diseases 6,7 suggest a myelopulmonary pathophysiologic link. In support of this concept, competent hematopoietic progenitors are required for disease development in the monocrotaline-or hypoxia-induced murine models of pulmonary hypertension, and BM transplantation can transfer disease to healthy naive mice. 8 In contrast to developmental origins of blood cells and vascular endothelium from the common hemangioblast, hematopoietic stem cells in the adult do not differentiate into endothelium, but rather promote postnatal angiogenesis and homeostasis in a paracrine fashion. [9][10][11][12] In the hierarchy of adult hematopoietic stem cell differentiation, a small pool of pluripotent, BMresident stem cells exhibit self-renewal and long-term survival. 13 These stem cells proliferate and differentiate into relatively shortlived multipotent progenitors that give rise to common lymphoid and common myeloid progenitors. Common lymphoid progenitors further differentiate into B-or T cell-committed precursors. The common myeloid progenitors proliferate and differentiate into bipotent common erythroid/megakaryocyte progenitors and into multipotent monocyte/granulocyte progenitors. These lineagerestricted myeloid progenitors differentiate into mature blood cells via unilineage-committed intermediate precursors. The hierarchy of proliferation and differentiation is at each bifurcation strictly regulated by lineage-specific transcription factors. 13 In the BM, the cell-surface glycoprotein CD133 is highly expressed on immature progenitors, allowing CD133 expression to define the population of hematopoietic progenitors. Functional analysis of human BM-derived CD133 ϩ cells indicates that this fraction is enriched in primitive multilineage hematopoietic stem cells. 14 Early outgrowth pro...

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Section: Discussionmentioning

confidence: 98%

Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

Asosingh

Farha

Lichtin

et al. 2012

Blood

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“…Previously, we found that radiation-induced pulmonary vascular remodeling is an important factor in the development of RILT resulting in pulmonary hypertension and RV hypertrophy that eventually leads to cardiopulmonary dysfunction [14,15]. In Fig.…”

Section: Ace Inhibition Does Not Protect the Pulmonary Vasculature Afmentioning

confidence: 98%

“…RILT traditionally is divided into an early inflammatory phase, termed ''radiation pneumonitis'', and a late fibro productive phase, termed ''fibrosis''. Recently, in a preclinical model, we found that, in concert with inflammation, radiation-induced vascular remodeling played a major role in the etiology of early RILT [14]. It was shown that lung irradiation induced early pulmonary vascular remodeling which resulted in pulmonary hypertension and right ventricle (RV) hypertrophy which eventually lead to cardiopulmonary dysfunction.…”

Section: Introductionmentioning

confidence: 97%

ACE inhibition attenuates radiation-induced cardiopulmonary damage

Veen

Ghobadi

Boer

et al. 2015

Radiotherapy and Oncology

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“…The inflammatory responses appear to dictate the severity of lung remodeling, but overall, this form of lung fibrosis is associated with low mortality (106). Regarding a major feature of this model, the pulmonary vascular remodeling that occurs is reminiscent of pulmonary arterial hypertension (110). The pathobiology of irradiation-induced fibrosis is believed to involve free radical-mediated DNA damage and the induction of TGF-b.…”

Section: Radiation-induced Fibrosismentioning

confidence: 99%

Animal Models of Fibrotic Lung Disease

Moore

Lawson

Oury

et al. 2013

Am J Respir Cell Mol Biol

341

308

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Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell-cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease.Keywords: fibrosis; collagen; fibroblast; aging; cytokines Interstitial lung disease is often associated with the development of chronic fibrosis. These diseases are characterized clinically by progressive dyspnea, cough, restrictive physiology, and impaired gas exchange. Humans manifest many types of fibrotic lung disease (1). Among the diffuse parenchymal lung disorders (DPLDs) are diseases of known cause (e.g., drug-related, environmental exposures, or those associated with collagen vascular disease), the idiopathic interstitial pneumonias (IIPs), the granulomatous DPLDs (e.g., sarcoidosis), and rare noncategorized diseases, such as lymphangioleiomyomatosis. Idiopathic pulmonary fibrosis (IPF) is the most common disease within the category of IIPs, and is histopathologically identified as usual interstitial pneumonia (UIP). Additional diseases within the IIP category include desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, and nonspecific interstitial pneumonia (NSIP). IPF carries a poor prognosis, with a mean survival time of less than 5 years after diagnosis (2-5). Biopsies from a single patient can show heterogenous patterns consistent with both UIP and NSIP (4, 6, 7), suggesting that NSIP shares common pathogenic mechanisms with UIP.Diagnoses of patients with IPF who do not exhibit classic high-resolution computed tomography scan changes are confirmed by histopathologic evaluations of surgical lung biopsies, which demonstrate the pattern of UIP. Hallmark features of UIP include epithelial cell hyperplasia, basement membrane denudation, alveolar consolidation, and fibroblastic foci in a pa...

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Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Cited by 66 publications

References 61 publications

Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

ACE inhibition attenuates radiation-induced cardiopulmonary damage

Animal Models of Fibrotic Lung Disease

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