Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

Penke, L.R.K.; Speth, John D.; Wettlaufer, Scott H.; Draijer, Christina; Peters‐Golden, Marc

doi:10.1101/2021.02.26.433086

Cited by 3 publications

(3 citation statements)

References 57 publications

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“…Bortezomib has previously been shown to significantly reduce lung fibrosis in Blm treated mice in two other studies, although it was suggested its effects were through inhibition of transforming growth factor beta signalling (56) or by modulating fibroblast function independent of proteasome inhibition (57). In this study we confirmed that bortezomib reduced lung fibrosis in Blm treated mice but also showed almost complete depletion of PCs in bortezomib treated lung tissue.…”

Section: Discussionsupporting

confidence: 82%

Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B cells that accumulate in the lung adjacent to areas of active fibrosis. We have previously shown a requirement for B cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20-B cell ablation did not reduce fibrosis in this model, however immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20 treated mice retained a high frequency of CD19+ CD138+ plasma cells (PCs). Interestingly, high levels of CD138+ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes PCs, reduced the level of Blm-induced lung fibrosis, implicating PCs as important effector cells in the development and progression of pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 82%

Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis

et al. 2022

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“…Several groups have sought to target degradative mechanisms in hepatic and extrahepatic disease through inhibiting the proteosome or autophagy. Bortezomib, a proteosome inhibitor used to treat Multiple Myeloma, reduces liver fibrosis in cholestatic mouse models (MDR2 −/− Bile duct ligation), as well as renal and lung fibrosis in other mouse models (Anan et al, 2006a;Jalan-Sakrikar et al, 2019;Zhou et al, 2019;Penke et al, 2021). The mechanisms associated with the fibrosis reduction differ, with focus on EZH2, TGFβ signaling, or limiting fibroblast activation, but the antifibrotic results were similar.…”

Section: Targeting Protein Degradation In Liver Fibrosismentioning

confidence: 99%

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Duwaerts

Maiers

2022

Front. Mol. Biosci.

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The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.

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“…Egyptian Journal of Cell and Tissue Research (EJCTR), Volume 2, Issue 1, January, 2024 ___________________________________________________________________________ It was hypothesized that in idiopathic pulmonary fibrosis (IPF), chronic and repetitive alveolar epithelial cell injury occurs with subsequent release of various cytokines as transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), fibroblast growth factor (FGR) and vascular endothelial growth factor (VEGF) (18) . TGFβ was clarified to be the main contributor of disease progression (19) .…”

Section: Groupsmentioning

confidence: 99%

Comparative Histological Study of the Possible Protective Effect of Valsartan Versus Dexamethasone On Cyclophosphamide-Induced Lung Injury in Adult Male Albino Rat

Abdel Lattif,

Abdel Aziz,

Mohamed

et al. 2024

Egyptian Journal of Cell and Tissue Research

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Introduction: Interstitial lung diseases are groups of chronic lung diseases characterized by inflammation and fibrosis. Aim of work: The present study was performed to evaluate the possible protective effect of valsartan versus dexamethasone on cyclophosphamide-induced lung injury in adult male albino rat. Material and Methods: Thirty male albino Rats were divided into 6 groups; 5 rats each: group I (Control), group II (Cyclophosphamide), group III (Valsartan), group IV (Dexamethasone), group V (Dexamethasone & Cyclophosphamide), and group VI (Valsartan and Cyclophosphamide). Lung specimens were taken on the 6 th day of experiment. Specimens were subjected to histological (Hematoxylin and Eosin, Periodic Acid-Schiff, and Masson's trichrome) and immunohistochemical (Alpha smooth muscle actin, Clsuter of Differentiation 86, and inducible Nitric Oxide Synthase) studies. Also, morphometric studies and statistical analysis were done. Results: Features of acute lung injury appeared in group II as thickening of interalveolar septa, narrowing of alveoli, and cellular infiltrations. There were significant increases in the mean area percentage of collagen fibers, inducible Nitric Oxide Synthase and Alpha smooth muscle actin, besides significantly increased number of Periodic Acid-Schiff -positive goblet cells and alveolar macrophages in anti-Clsuter of Differentiation 86 immuostained sections, and thickness of interalveolar septa.Sections in group V and group VI demonstrated that lung tissue restored normal histological and immunohistochemical results, compared to group II. There was a significant decrease in mean area percentage of collagen fibers, inducible Nitric Oxide Synthase and Alpha smooth

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Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

Cited by 3 publications

References 57 publications

Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis

Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Comparative Histological Study of the Possible Protective Effect of Valsartan Versus Dexamethasone On Cyclophosphamide-Induced Lung Injury in Adult Male Albino Rat

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