Mesenchymal Stromal Cells in Animal Bleomycin Pulmonary Fibrosis Models: A Systematic Review

Srour, Nadim; Thébaud, Bernard

doi:10.5966/sctm.2015-0121

Cited by 98 publications

(84 citation statements)

References 59 publications

(217 reference statements)

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“…IPF is a disease with a complex pathology, and simple anti‐inflammatory and antifibrotic approaches are not curative. Although the bleomycin model does not capture the full complexity of the disease, it does replicate the acute exacerbations of the disease [] where proinflammatory cytokines predominate (e.g., TNF‐α, IL‐1β, IL‐6, TGF‐β, fibronectin, and procollagen‐1) []. Furthermore, at the early stages of inflammation, when PGE2 and LTB4 provoke neutrophil extravasation, LXA4 and its epimer 15‐epi‐LXA4 was shown to have a profound inhibitory effect on PMN infiltration in vivo [].…”

Section: Discussionmentioning

confidence: 99%

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Tan

Muljadi

et al. 2016

Stem Cells Translational Medicine

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Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4 (LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085–1095

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Section: Discussionmentioning

confidence: 99%

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Tan

Muljadi

et al. 2016

Stem Cells Translational Medicine

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“…Fibrotic deposition in the i.p . BLM model is observed in the subpleural areas of the lung that is also observed in IPF patients and is thus more clinically relevant (Degryse & Lawson, ; Della Latta, Cecchettini, Del Ry, & Morales, ; Moore et al., ; Srour & Thébaud, ). Chronic i.p .…”

Section: Introductionmentioning

confidence: 93%

“…administration of BLM causes a more persistent fibrotic response that is typically non-reversible (Ask et al, 2008;Degryse & Lawson, 2011;Pardo et al, 2005). Using this experimental model of lung fibrosis that more closely resembles the clinical presentation of IPF (Degryse & Lawson, 2011;Della Latta et al, 2015;Moore et al, 2013;Srour & Thébaud, 2015), our aim was to identify temporal changes in respiratory system mechanics that are also observed in IPF patients. Identification of early changes in lung mechanics in this model that are more closely aligned with physiological measurements in patients (Carrington et al, 2018) will be essential to guide future drug development efforts.…”

Section: • What Is the Central Question Of This Study?mentioning

confidence: 99%

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Headley

Wilson

et al. 2018

Experimental Physiology

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New Findings What is the central question of this study?When do alterations in pulmonary mechanics occur following chronic low‐dose administration of bleomycin? What is the main finding and its importance?Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single‐frequency forced oscillation manoeuvres and pressure–volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic. Abstract Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure–volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure–volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.

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“…The role of MSCs in bleomycin induced lung fibrosis is controversial with some studies claiming that MSCs are protective in mice challenged with bleomycin whereas others indicating that these cells are protective only when given preventatively prior to bleomycin instillation. Still other studies have not reported any beneficial effect of these cells (reviewed in [55]). Further, a Phase 1b study addressing the safety of the infusion of placental derived mesenchymal stromal cells in IPF patients failed to show any significant changes in Forced Vital Capacity (FVC), Diffusing Capacity of the lungs for Carbon Monoxide (DLCO), 6-minute walk distance or CT fibrosis score, at 6 months after a single infusion of 1–2 million cells intravenously[56].…”

Section: Fibroblast and Myofibroblasts Heterogeneity In Injured Murinmentioning

confidence: 99%

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Habiel

Hogaboam

2017

Curr Pathobiol Rep

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Purpose of review Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung diseases of unknown eathiopathogenesis, mean survival of 3-5 years and limited therapeutics. Characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, considerable effort was undertaken to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized. Recent findings Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes and mesothelial cells differentiate into myofibroblasts. However, epithelial and bone marrow derived cells may give rise to collagen expressing fibroblasts but do not differentiate into myofibroblasts. Summary There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte derived myofibroblasts and loss of lipofibroblasts and lipofibroblast derived myofibroblasts in IPF.

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Mesenchymal Stromal Cells in Animal Bleomycin Pulmonary Fibrosis Models: A Systematic Review

Cited by 98 publications

References 59 publications

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

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