The Role of TGF-β in Bleomycin Induced Pulmonary Fibrosis

Khalil, Nasreen; O’Connor, Robert

doi:10.1007/978-1-59745-292-2_36

Cited by 3 publications

(5 citation statements)

References 78 publications

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“…This accumulation is associated with increases in the levels of systemic and microenvironmental pro-inflammatory cytokines (TGF-β, CXCL1 and others), which precede the appearance of the pro-fibrotic markers (fibronectin and pro-collagen 1) and of fibrosis 5 . Abnormal expression of P-SEL by endothelial cells 10 and of TGF-β by numerous cell types, including endothelial cells, epithelial cells, alveolar type II cells and macrophages 53,54 , has been implicated in the development of fibrosis in the lungs of bleomycin-treated animals. High levels of TGF-β produced by the alveolar Type II cells were also associated with the development of fibrosis in the Tamoxifen-treated SP-CI73T mouse model 25 .…”

Section: Discussionmentioning

confidence: 99%

“…This accumulation is associated with an increase in the levels of systemic and microenvironmental pro-inflammatory cytokines (TGF-β, CXCL1 and others), which precede pro-fibrotic markers (fibronectin and procollagen 1), eventually leading to fibrosis 5 . Abnormal expression of P-SEL by endothelial cells 10 and of TGF-β by numerous cell types, including endothelial cells, epithelial cells, type II pneumocytes and alveolar macrophages 50,51 , has been implicated in the development of fibrosis in the lungs of bleomycin-treated animals. In addition, although CXCL1 is elevated in broncoalveolar lavages of these mice 58 , the cells responsible for its production are not yet been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Previous results in bleomycin mice have indicated that IPF is associated with greater than normal expression of several pro-inflammatory factors including P-SEL (high in endothelial cells); TGF-β (produced by multiple cell types including alveolar macrophages, epithelial and endothelial cells, interstitial fibroblasts and alveolar Type II cells); and CXCL1, the murine equivalent of human interleukin-8 (IL-8) in bronchoalveolar lavages 10, [49][50][51][52][53][54][55][56][57][58][59] . High levels of TGF-β are also expressed by the alveolar Type II cells of the Tamoxifen-driven conditional knock-in SPTFCI73T mouse model 25 .…”

Section: Lungs From Old Wt and Gata1 Low Mice Contain Elevated Levels...mentioning

confidence: 99%

“…Previous described results in mice indicated that in the bleomycin model, IPF is associated with greater than normal expression of several pro-inflammatory factors including: P-selectin (produced by endothelial cells); TGF-β (produced by several cell types including alveolar macrophages, epithelial and endothelial cells, interstitial fibroblasts and Type II pneumocytes); and CXCL1, the murine equivalent of human interleukin-8 (IL-8) in bronchoalveolar lavages 10,46-10 patients 10,[46][47][48][49][50][51][52][53][54][55][56] .…”

Section: Lungs From Old Gata1 Low Mice Contain Elevated Levels Of P-s...mentioning

confidence: 99%

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GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

Migliaccio

Zingariello

Verachi

et al. 2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and Gata1low mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, Gata1low mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by P-selectin deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, Gata1low mice are the first genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Lungs From Old Wt and Gata1 Low Mice Contain Elevated Levels...mentioning

confidence: 99%

Section: Lungs From Old Gata1 Low Mice Contain Elevated Levels Of P-s...mentioning

confidence: 99%

See 2 more Smart Citations

GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

Migliaccio

Zingariello

Verachi

et al. 2023

Preprint

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“…BLM exerts anti-tumorigenic effects by inducing DNA strand destruction in cancer cells [ 17 , 18 ]; however, it has deadly side effects, causing fibrosis in patients [ 19 , 20 ]. BLM has been shown to increase ROS production in pulmonary alveolar tissues and induce inflammatory cell activation, such as macrophage activation and infiltration in connective tissues [ 21 ]. Moreover, BLM-induced ROS is implicated in the conversion of TGF-β from a latent to an active form in alveolar epithelial cells [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Echinochrome A Treatment Alleviates Fibrosis and Inflammation in Bleomycin-Induced Scleroderma

et al. 2021

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Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.

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Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice

Karhadkar

Pilling

2021

PLoS ONE

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SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.

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The Role of TGF-β in Bleomycin Induced Pulmonary Fibrosis

Cited by 3 publications

References 78 publications

GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

Echinochrome A Treatment Alleviates Fibrosis and Inflammation in Bleomycin-Induced Scleroderma

Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice

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