Targeted drug delivery via caveolae-associated protein PV1 improves lung fibrosis

Marchetti, Gabriela M.; Burwell, Timothy; Peterson, Norman C.; Cann, Jennifer A.; Hanna, Richard N.; Li, Qing; Boyd, Jonathan T.; Kennedy, Maureen A.; Zhao, Weiguang; Rickert, Keith; Grimsby, Joseph; Dall’Acqua, William F.; Wu, Herren; Tsui, Ping; Borrok, M. Jack

doi:10.1038/s42003-019-0337-2

Cited by 26 publications

(30 citation statements)

References 25 publications

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“…Our dual effect on both acute inflammation and chronic fibrosis, as well as our finding that pulmonary endothelial cells, mast cells, and macrophages are highly 15-PGDH active, suggest multiple discrete mechanisms contribute to PGDHi-mediated protection. These results also indicate that systemic 15-PGDH inhibition may exert a more potent protective effect than targeted PGE2 delivery to endothelial cells 21 or alveolar macrophages 22 during IPF. Early in disease, PGDHi may improve alveolar epithelial wound repair, in a manner similar to that which has been demonstrated in the colonic epithelium 26 .…”

Section: Discussionmentioning

confidence: 72%

“…Therefore, well-tolerated strategies to increase pulmonary PGE2 levels are likely to mitigate pathogenesis. Indeed, recent reports have demonstrated that either systemic administration of the long-acting PGE2 analog 16,16-dimethyl-PGE2 18 , or targeted PGE2 delivery via pulmonary endothelial cell-specific antibodies or inhalation of PGE2-loaded liposomes 21 , 22 demonstrate therapeutic efficacy in murine pulmonary fibrosis. In vitro , PGE2 stimulation or EP2/EP4-specific agonism abrogates myofibroblast differentiation and expression of ECM genes in TGFβ-treated human pulmonary fibroblasts and in fibroblasts derived from IPF patients 19 , 23 – 25 .…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Smith

Witkin

Jogasuria

et al. 2020

Sci Rep

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycintreated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Smith

Witkin

Jogasuria

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Our dual therapeutic effect on both acute inflammation and chronic fibrosis, as well as, our finding that pulmonary endothelial cells, mast cells, and macrophages are highly 15-PGDH active, suggest multiple discrete mechanisms contribute to PGDHi-mediated protection. These results also indicate that systemic 15-PGDH inhibition may exert a more potent protective effect than targeted PGE2 delivery to endothelial cells 21 or alveolar macrophages 22 during IPF. Early in disease, PGDHi may improve alveolar epithelial wound repair, in a manner similar to that which has been demonstrated in the colonic epithelium 26 .…”

Section: Discussionmentioning

confidence: 72%

Therapeutic Targeting of 15-PGDH in Murine Idiopathic Pulmonary Fibrosis

Witkin

et al. 2019

Preprint

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1Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial 2 remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but 3 involves pathologic inflammation and subsequent failure to resolve fibrosis in response to 4 epithelial injury. Therapeutic strategies for IPF are limited to anti-inflammatory and 5 immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts 6TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to 7 raise tissue PGE2 during IPF have been limited. We previously described the discovery of a 8 small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-9 hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we 10 evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-11 PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced IPF. Long-term 12PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular 13 matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, 14PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. 15 Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-16 PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine IPF, 17 and may have clinical utility to treat human disease. 18 19 Article summary: In IPF, lung epithelial injury leads to local inflammation and fibrosis, which 22 impairs pulmonary function. Inhibition of 15-PGDH using a well-tolerated small molecule 23 3 attenuates inflammation and prevents pulmonary fibrosis and dysfunction in a mouse model of 1 bleomycin-induced IPF. 2 3 15-PGDH is highly expressed and active in healthy murine lung tissue PGDHi attenuates pulmonary measurements of tissue stiffness in bleomycin-treated 24 mice

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“…107 They found that there was a significant correlation between the levels of EV miR-21-5p and the rate of decline in predicted vital capacity of the lung over 6 months. 108 Carleo et al 109 investigated potential biomarkers for familial IPF. They showed protein associated with clathrin-coated vesicles were part of a group of proteins upregulated in familial IPF.…”

Section: Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

“…Using EV associated proteins for targeted therapies is relatively understudied. Marchetti et al 108 developed antiplasmalemma vesicle-associated protein (PV1) antibodies to enhance therapeutic delivery to the lungs. The PV1 antibody was conjugated to an antifibrotic small molecule and showed increased localisation of the small molecule to the lung and kidneys.…”

Section: Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

Role of extracellular vesicles in chronic lung disease

Trappe

Donnelly

McNally

et al. 2021

Thorax

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To explore the role of extracellular vesicles (EVs) in chronic lung diseases.EVs are emerging as mediators of intercellular communication and possible diagnostic markers of disease. EVs harbour cargo molecules including RNA, lipids and proteins that they transfer to recipient cells. EVs are intercellular communicators within the lung microenvironment. Due to their disease-specific cargoes, EVs have the promise to be all-in-one complex multimodal biomarkers. EVs also have potential as drug carriers in chronic lung disease.Descriptive discussion of key studies of EVs as contributors to disease pathology, as biomarkers and as potential therapies with a focus on chronic obstructive pulmonary disorder (COPD), cystic fibrosis (CF), asthma, idiopathic pulmonary fibrosis and lung cancer.We provide a broad overview of the roles of EV in chronic respiratory disease. Recent advances in profiling EVs have shown their potential as biomarker candidates. Further studies have provided insight into their disease pathology, particularly in inflammatory processes across a spectrum of lung diseases. EVs are on the horizon as new modes of drug delivery and as therapies themselves in cell-based therapeutics.EVs are relatively untapped sources of information in the clinic that can help further detail the full translational nature of chronic lung disorders.

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Targeted drug delivery via caveolae-associated protein PV1 improves lung fibrosis

Cited by 26 publications

References 25 publications

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Therapeutic Targeting of 15-PGDH in Murine Idiopathic Pulmonary Fibrosis

Role of extracellular vesicles in chronic lung disease

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