Lung-targeted delivery of TGF-β antisense oligonucleotides to treat pulmonary fibrosis

Kim, Jung-Hyun; Jeon, Seulgi; Kang, Seong Jae; Kim, Kyoung Ran; Thai, Hien Bao Dieu; Lee, Seokyung; Kim, Sehoon; Lee, Yun Sil; Ahn, Dae Ro

doi:10.1016/j.jconrel.2020.03.016

Cited by 23 publications

(7 citation statements)

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“…Some studies suggested that TNF‐α plays a vital role in the pathogenesis of pulmonary fibrosis, and its expression level can judge the development process and activity of the lesion 9,28,29 . TGF‐β is considered as one of the main cytokines that aggravates pulmonary fibrosis, besides, TGF‐β is one of cytokines that is associated with resolution of inflammation 8,30 …”

Section: Discussionmentioning

confidence: 99%

“…9,28,29 TGF-β is considered as one of the main cytokines that aggravates pulmonary fibrosis, besides, TGF-β is one of cytokines that is associated with resolution of inflammation. 8,30 Autophagy is subdivided into macroautophagy and chaperonemediated autophagy according to different lysosomal pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have shown that pulmonary fibrosis was activated by a variety of fibrogenic factors and cytokines were released in pathogenesis. Among these cytokines, tumor necrosis factor (TNF‐α) and transforming growth factor (TGF‐β) are two crucial modulators in the regulating of inflammatory and fibrogenic responses to SiO 2 ‐exposed 8,9 …”

Section: Introductionmentioning

confidence: 99%

“…Among these cytokines, tumor necrosis factor (TNF-α) and transforming growth factor (TGF-β) are two crucial modulators in the regulating of inflammatory and fibrogenic responses to SiO 2 -exposed. 8,9 Autophagy is a critical cellular degradative pathway that participates in physiological and pathological maintaining cell homeostasis and death. [10][11][12] Moreover, autophagy refers to a collection of catabolic pathways that transport components of the cytoplasm to lysosomes for degradation, which can induce inflammatory damage in the progression of pulmonary fibrosis.…”

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confidence: 99%

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Silica dust exposure induces pulmonary fibrosis through autophagy signaling

Shi

Wang³

et al. 2021

Environmental Toxicology

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Silicosis is a well‐acknowledged occupational lung disease caused by inhalation of a large amount of free silica dust during the production period and eventually a considerable negative impact on the patients' quality of life. Autophagy exerts a critical influence on immune and inflammatory responses during the pathogenesis of pulmonary fibrosis. In this study, we sought to determine whether autophagy is involved in silicosis's pathogenesis and how it may affect pulmonary cellular physiology. In the animal experiments, we found persistent activation of autophagy in the development of pulmonary fibrosis, which was also accompanied by tumor necrosis factor and transforming growth factor expression increased. Therefore, the autophagy signaling pathway may regulate the inflammatory response and affect the progression of fibrosis. Further, in vitro experiments, we used LY294002, RAPA, and N‐acetylcysteine (NAC) intervened autophagy. Our results showed that PI3K/Akt/mTOR signaling pathway is involved in the autophagy changed mediated by SiO2 exposed, and autophagy might play a protective role in the progression of pulmonary fibrosis. Additionally, NAC's effect is not apparent on SiO2‐mediated autophagy through the PI3K/Akt/mTOR signaling pathway, but it can reduce the inflammatory response on NR8383 cells mediated by SiO2‐exposed. Nevertheless, it's interesting that NAC can reduce the inflammatory response on NR8383 cells mediated by SiO2‐exposed. Taken together, our data demonstrated that SiO2‐exposed can induce pulmonary fibrosis along with autophagy both in vivo and in vitro, NAC could alleviate the inflammatory response NR8383 cells by SiO2‐exposed through non PI3K/Akt/mTOR signaling pathway, and the specific mechanism of its action needs further studying.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Silica dust exposure induces pulmonary fibrosis through autophagy signaling

Shi

Wang³

et al. 2021

Environmental Toxicology

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“…Since TGF-β/Smad3 signaling is a critical factor for ECM gene expression, regulation of this signaling has been considered a potential approach for treatment of PF ( Cushing et al, 2011 ; Xiao et al, 2012 ; He et al, 2013 ; Montgomery et al, 2014 ). For example, TGF-β antisense oligonucleotides has been delivered and targeted to lung to treat PF ( Kim et al, 2020 ). In PF, TGF-β suppressed the level of miR-29 leading to the overexpression of collagens-related genes suggesting that miR-29 is an important mediator of TGF-β/Smad3 signaling.…”

Section: Discussionmentioning

confidence: 99%

The Extracellular Matrix Enriched With Exosomes for the Treatment on Pulmonary Fibrosis in Mice

Zhao

Liu

et al. 2021

Front. Pharmacol.

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Pulmonary fibrosis (PF) is a severe respiratory disease caused by lung microenvironment changes. TGF-β/Smad3 signaling pathway plays a critical role in the fibrotic process. MicroRNA-29 (miR-29) has proved to alleviate the occurrence of PF by downregulating TGF-β/Smad3 signaling pathway. The miRNA application encounters obstacles due to its low stability in body and no targeting to lesions. Exosomes can be used for therapeutic delivery of miRNA due to their favorable delivery properties. However, low efficiency of separation and production impedes the therapeutic application of exosomes. In this study, we developed a liquid natural extracellular matrix (ECM) enriched with miR-29-loaded exosomes for PF treatment. The collagen-binding domain (CBD)-fused Lamp2b (CBD-Lamp2b) and miR-29 were overexpressed in human foreskin fibroblast (HFF) host cells for the entrapment of miR-29-loaded exosomes in ECM of the cells. The repeated freeze-thaw method was performed to prepare the liquid ECM enriched with exosomes without destroying the exosomal membrane. In summary, this study developed a novel functional ECM biomaterial for therapy of PF, and also provided a promising gene therapy platform for different diseases by treatment with liquid ECM that is, enriched with exosomes loaded with different functional miRNAs.

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A Two‐Pronged Pulmonary Gene Delivery Strategy: A Surface‐Modified Fullerene Nanoparticle and a Hypotonic Vehicle

et al. 2021

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Inhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)‐based nanoparticles with non‐adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two‐pronged delivery strategy provides safe, wide‐spread and high‐level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.

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Lung-targeted delivery of TGF-β antisense oligonucleotides to treat pulmonary fibrosis

Cited by 23 publications

References 50 publications

Silica dust exposure induces pulmonary fibrosis through autophagy signaling

Silica dust exposure induces pulmonary fibrosis through autophagy signaling

The Extracellular Matrix Enriched With Exosomes for the Treatment on Pulmonary Fibrosis in Mice

A Two‐Pronged Pulmonary Gene Delivery Strategy: A Surface‐Modified Fullerene Nanoparticle and a Hypotonic Vehicle

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