Transgenic up-regulation of Claudin-6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation

Lewis, Joshua B; Bodine, Jared S; Gassman, Jason R.; Arce, Samuel; Milner, Dallin; Dunaway, Todd; Egbert, Kaleb M; Monson, Troy; Broberg, Dallin S.; Arroyo, Juan A.; Reynolds, Paul

doi:10.1007/s11356-018-1985-3

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…Slides were stained using Wright’s Stain and imaged at 1000× on the Olympus BX51 Microscope 77 . A total of 200 cells were differentially counted for macrophages, lymphocytes, and polymorphonucleocytes in duplicate and cell counts were averaged 78 .…”

Section: Methodsmentioning

confidence: 99%

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

Roy,

Shi,

Chang

et al. 2023

Nat Commun

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The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

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Section: Methodsmentioning

confidence: 99%

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

Roy,

Shi,

Chang

et al. 2023

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Tissues were harvested at the conclusion of the study period and following a 6 h fast and 24 h after the final exposure. Lungs were lavaged for assessment and capturing of bronchoalveolar lavage fluid (BALF), as described previously [11,32]. Total numbers of cells were counted using a hemocytometer with trypan blue exclusion.…”

Section: Methodsmentioning

confidence: 99%

Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics

Gibbs

Dallon

Lewis

et al. 2019

IJMS

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Diesel exhaust particles (DEPs) are known pathogenic pollutants that constitute a significant quantity of air pollution. Given the ubiquitous presence of macrophages throughout the body, including the lungs, as well as their critical role in tissue and organismal metabolic function, we sought to determine the effect of DEP exposure on macrophage mitochondrial function. Following daily DEP exposure in mice, pulmonary macrophages were isolated for mitochondrial analyses, revealing reduced respiration rates and dramatically elevated H2O2 levels. Serum ceramides and inflammatory cytokines were increased. To determine the degree to which the changes in mitochondrial function in macrophages were not dependent on any cross-cell communication, primary pulmonary murine macrophages were used to replicate the DEP exposure in a cell culture model. We observed similar changes as seen in pulmonary macrophages, namely diminished mitochondrial respiration, but increased H2O2 production. Interestingly, when treated with myriocin to inhibit ceramide biosynthesis, these DEP-induced mitochondrial changes were mitigated. Altogether, these data suggest that DEP exposure may compromise macrophage mitochondrial and whole-body function via pathologic alterations in macrophage ceramide metabolism.

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“…CLDN6 overexpression impacted secondhand tobacco smoke (SHS)-induced inflammation in the lung by reducing total bronchoalveolar lavage fluid (BALF) protein, cells, and secreted pro-inflammatory cytokines [40]. Similarly, CLDN6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation in the same way [41]. Taken together, epithelial barriers organized by CLDN6 reduce cigarette or diesel-induced inflammation in the lung.…”

Section: The Lung Epithelial Barriermentioning

confidence: 98%

CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers

Qiu

Quan

2021

IJMS

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Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.

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Transgenic up-regulation of Claudin-6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation

Cited by 6 publications

References 59 publications

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics

CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers

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