Genetic Ablation of Mast Cells Redefines the Role of Mast Cells in Skin Wound Healing and Bleomycin-Induced Fibrosis

Willenborg, Sebastian; Eckes, Beate; Brinckmann, Jürgen; Krieg, Thomas; Waisman, Ari; Hartmann, Karin; Roers, Axel; Eming, Sabine A.

doi:10.1038/jid.2014.12

Cited by 66 publications

(63 citation statements)

References 36 publications

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“…Concerning the ECM cross-link status of mouse lungs following hyperoxia exposure, the abundance of the DHLNL collagen cross-link, as well as the DHLNL/HLNL, was increased in lungs from hyperoxia-exposed mice, suggestive of a profibrotic state (17,63). The application of BAPN concomitantly with hyperoxia blunted this increase in lung collagen accumulation and partially normalized the DHLNL/HLNL.…”

Section: Discussionmentioning

confidence: 95%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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RE. Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. Am J Physiol Lung Cell Mol Physiol 308: L1145-L1158, 2015. First published April 3, 2015 doi:10.1152/ajplung.00039.2015.-Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O 2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor ␤-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, ␤-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. lung development; elastin; collagen; lysyl oxidase; alveolarization POSTNATAL LUNG DEVELOPMENT in mice is characterized by a period of intensive growth and remodeling of the lung parenchyma, which rapidly (over a period of days) generates a large number of small alveoli and thus maximizes the alveolar surface area over which gas exchange can take place. Secondary septation, the generation of new septa from preexisting septa, which then divide the air spaces, peaks in mice between 4 and 7 days after birth and is largely complete 21 days after birth. In humans, secondary septation is already well underway during late stages of pregnancy, and thus occurs in utero, and continues several years into postnatal life. Disturbances to the formation of secondary septa, such as the arrested secondary septation associated with bronchopulmonary dysplasia (BPD) in humans, leads to malformed lung...

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Section: Discussionmentioning

confidence: 95%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A study on systemic sclerosis [16], cell-to-cell contact between mast cells and fibroblasts was observed but the authors were unable to determine whether the contact was a characteristic specific to systemic sclerosis or due to mast cell activation. In this study cell-to-cell contact between fibroblasts and mast cells was also (2014) has shown that genetic ablation of connective tissue type mast cells fails to prevent bleomycin induced lung fibrosis [45]. Keloid fibroblasts have been isolated from keloid tissue and grown in cell culture; compared to normal cells keloid fibroblasts have shown differences in growth properties and gene expression [46,47].…”

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confidence: 81%

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Arbi

Eksteen

Oberholzer

et al. 2015

Ultrastructural Pathology

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Keloids are benign hyper-proliferative growths of fibrous tissue, where increased fibroblast activity results in abnormal collagen deposition. Excessive inflammation is a characteristic feature of keloids but little is known about the underlying ultrastructural features of keloids related to collagen processing, fibril and fibre formation, the interaction between fibroblasts and associated collagen fibres and mast cells. In this study, the ultrastructure of the dermis of keloid patients was evaluated using light and transmission electron microscopy techniques. Abnormal intracellular premature collagen fibril formation was observed. Phagocytosis of collagen fibrils by mast cells was a common ultrastructural feature of keloid tissue as was a close or direct 2 association between fibroblasts and mast cells. Based on these findings and recent advances in knowledge related to collagen synthesis, fibril formation and processing we hypothesise that keloid formation is primary due to abnormal collagen synthesis where the consequent accumulation of collagen fibres causes increased mast cell recruitment and collagen phagocytosis. Subsequent release of mast cell derived mediators then promotes further collagen synthesis. The observation of early formation in keloid tissue of premature insoluble collagen fibrils supports previous studies that enzymes such as procollagen C-proteinase are important early therapeutic targets.

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“…Moreover, chymase inhibitor alleviated skin fibrosis in tight skin mice [45] . However, in the bleomycin induced scleroderma experiments with mast cell deficient Kit W/W-V mice [46] and genemodified Mcpt5Cre/iDTR mice [47] scleroderma was induced regardless of the presence or absence of mast cells. These findings suggest that the involvement of mast cells is limited, and further investigation using different models is necessary.…”

Section: Mast Cells In Systemic Sclerosismentioning

confidence: 99%

Mast cells in collagen diseases

Mikita

Inaba²,

Yoshimasu³

et al. 2017

Trends Immunother

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Mast cells are involved in many immune reactions and diseases through 1) the expressions of several receptors, 2) productions of various mediators such as histamine, cytokines, and chemokines, 3) direct in teractions with immune cells. Besides allergic diseases, the involvement of mast cells has been also in vestigated in autoimmune diseases such as bullous pemphigoid, rheumatoid arthritis, and multiple sclerosis. Moreover, several studies reported the involvement of mast cells in collagen diseases. In this article, we review recent findings about the role of mast cells especially in systemic lupus erythematosus and systemic sclerosis. In these diseases, mast cells seem to be involved in local inflammation and tissue damage in the targeted organ or local immunosuppression rather than the development of autoimmunity including production of autoantibodies.

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Genetic Ablation of Mast Cells Redefines the Role of Mast Cells in Skin Wound Healing and Bleomycin-Induced Fibrosis

Cited by 66 publications

References 36 publications

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Mast cells in collagen diseases

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