Steroid resistance in COPD is associated with impaired molecular chaperone HSP90 expression by pro-inflammatory lymphocytes

Hodge, Greg; Jersmann, Hubertus; Tran, Hai B.; Roscioli, Eugene; Holmes, Mark; Reynolds, Paul N.; Hodge, Sandra

doi:10.1183/13993003.congress-2016.pa4655

Cited by 5 publications

(11 citation statements)

References 17 publications

(28 reference statements)

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“…These cytotoxic, pro-in ammatory lymphocytes showed increased expression of granzyme b/ perforin and IFNγ/TNFα compared to their CD28+ counterparts. Importantly, these senescent lymphocytes were resistant to the anti-in ammatory effects of glucocorticoids possibly due to increased expression of drug e ux pump p-glycoprotein 1 (Pgp-1) [7], decreased expression of glucocorticoid receptor (GCR) [8], histone deacetylase 2 (HDAC2) [9], and nuclear chaperone heat shock protein 90 (Hsp90) [10] and sirtuin 1 (SIRT1) [11]. These ndings may explain why glucocorticoids (GCS) fail to suppress in ammation in senescent lymphocytes in COPD.…”

Section: Introductionmentioning

confidence: 99%

BLTR1 is decreased in steroid resistant pro-inflammatory CD28nullCD8+ T lymphocytes in patients with COPD - the spillover hypothesis explained?

Hodge

Jersmann

Holmes

et al. 2022

Preprint

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Introduction: Pro-inflammatory CD8+ T cells are increased in the lungs of both smokers and COPD patients but also in the peripheral circulation in COPD. The reason for this is unclear but has been described as a spillover from cells in the lungs that may cause the systemic inflammation noted in COPD. We have recently shown an increase in steroid resistant CD28nullCD8+ senescent lymphocytes in the lungs and peripheral blood in COPD. Leukotreine B4 (LB4) receptor 1 (BLTR1) is involved in recruitment of CD8+ T cells to sites of inflammation and we hypothesized may be involved in migration of these senescent lymphocytes from the lungs in COPD. Methods: BLTR1, GCR, IFNγ and TNFαexpression were measured in peripheral blood, BAL and large proximal and small distal airway CD28± CD8± T and NKT-like cells from COPD patients and healthy control subjects (± prednisolone) following in vitro stimulation using flow cytometry and western blot. Chemotaxis of leucocyte subsets was determined (± LB4 ± prednisolone). Results: There was an increase in BLTR1-CD28nullCD8+ lymphocytes in the lungs and blood in patients with COPD compared with controls. BLTR1- CD28null CD8+ T and NKT-like cells produce more IFN/TNF than BLTR+ cells and fail to migrate to LTB4. Treatment with 1µM prednisolone in vitro resulted in upregulation of BLTR1 expression in pro-inflammatory CD28nullCD8+ cells and migration to LB4. Conclusions: Loss of BLTR1 is associated with an increased inflammatory potential of CD28nullCD8+ T cells and may allow these pro-inflammatory steroid resistant cells to migrate to peripheral blood. Treatment strategies that upregulate BLTR1 may reduce systemic inflammation and associated co-morbidity in patients with COPD.

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Section: Introductionmentioning

confidence: 99%

BLTR1 is decreased in steroid resistant pro-inflammatory CD28nullCD8+ T lymphocytes in patients with COPD - the spillover hypothesis explained?

Hodge

Jersmann

Holmes

et al. 2022

Preprint

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“…Western blot. As previously described 24 , protein was isolated from differentiated AEC cultures in situ from the transwell membrane surface using M-Per mammalian cell protein lysis reagent and Halt® protease and phosphatase inhibitor cocktail (both Thermo Scientific, Victoria, Australia). Protein samples were quantified using the BCA protein assay method (Bio-Rad, Victoria, Australia), and 10 μg electrophoresed using Novex® 4-12% gradient Bis-Tris denaturing gels (Life Technologies, Victoria, Australia) and electroblotted to Trans-Blot® Turbo nitrocellulose membranes (Bio-Rad).…”

Section: Scanning Electron Microscopy High-resolution Topographical E...mentioning

confidence: 99%

Organotypic sinonasal airway culture systems are predictive of the mucociliary phenotype produced by bronchial airway epithelial cells

Delhove

Alawami

Macowan

et al. 2022

Sci Rep

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Differentiated air–liquid interface models are the current standard to assess the mucociliary phenotype using clinically-derived samples in a controlled environment. However, obtaining basal progenitor airway epithelial cells (AEC) from the lungs is invasive and resource-intensive. Hence, we applied a tissue engineering approach to generate organotypic sinonasal AEC (nAEC) epithelia to determine whether they are predictive of bronchial AEC (bAEC) models. Basal progenitor AEC were isolated from healthy participants using a cytological brushing method and differentiated into epithelia on transwells until the mucociliary phenotype was observed. Tissue architecture was assessed using H&E and alcian blue/Verhoeff–Van Gieson staining, immunofluorescence (for cilia via acetylated α-tubulin labelling) and scanning electron microscopy. Differentiation and the formation of tight-junctions were monitored over the culture period (day 1–32) by quantifying trans-epithelial electrical resistance. End point (day 32) tight junction protein expression was assessed using Western blot analysis of ZO-1, Occludin-1 and Claudin-1. Reverse transcription qPCR-array was used to assess immunomodulatory and autophagy-specific transcript profiles. All outcome measures were assessed using R-statistical software. Mucociliary architecture was comparable for nAEC and bAEC-derived cultures, e.g. cell density P = 0.55, epithelial height P = 0.88 and cilia abundance P = 0.41. Trans-epithelial electrical resistance measures were distinct from day 1–14, converged over days 16–32, and were statistically similar over the entire culture period (global P < 0.001). This agreed with end-point (day 32) measures of tight junction protein abundance which were non-significant for each analyte (P > 0.05). Transcript analysis for inflammatory markers demonstrated significant variation between nAEC and bAEC epithelial cultures, and favoured increased abundance in the nAEC model (e.g. TGFβ and IL-1β; P < 0.05). Conversely, the abundance of autophagy-related transcripts were comparable and the range of outcome measures for either model exhibited a considerably more confined uncertainty distribution than those observed for the inflammatory markers. Organotypic air–liquid interface models of nAEC are predictive of outcomes related to barrier function, mucociliary architecture and autophagy gene activity in corresponding bAEC models. However, inflammatory markers exhibited wide variation which may be explained by the sentinel immunological surveillance role of the sinonasal epithelium.

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“…In the case of chaperones, circulating levels of HSP70 have been associated with an increased risk of COPD 40 . Additionally, the loss of Hsp90 expression in lymphocytes has been implicated in steroid resistance in COPD 41 . In relation to mechanisms involved in autophagy, scientific research is divided into evidence that demonstrates that the autophagy is excessive in COPD 42 , and studies showing that it could be defective 43 .…”

Section: Loss Of Proteostasis In Copdmentioning

confidence: 99%

Aging and Chronic Respiratory Diseases: Novel Mechanisms

Sellarés¹,

Rojas²

2017

BRN

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Aging is a progressive loss of physiological integrity leading to impaired function and increased vulnerability to death. Research into the mechanisms of aging could contribute to a better understanding of many chronic diseases. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic respiratory diseases associated with aging due to the fact that "accelerated" aging of the lung has been proposed as an important mechanism in both diseases. Many of the hallmarks that have been described in aging are also present in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion are all mechanisms of aging present in both diseases. In this review we will examine the underlying mechanisms that link aging with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. (BRN Rev. 2017;3:18-29)

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Steroid resistance in COPD is associated with impaired molecular chaperone HSP90 expression by pro-inflammatory lymphocytes

Cited by 5 publications

References 17 publications

BLTR1 is decreased in steroid resistant pro-inflammatory CD28nullCD8+ T lymphocytes in patients with COPD - the spillover hypothesis explained?

BLTR1 is decreased in steroid resistant pro-inflammatory CD28nullCD8+ T lymphocytes in patients with COPD - the spillover hypothesis explained?

Organotypic sinonasal airway culture systems are predictive of the mucociliary phenotype produced by bronchial airway epithelial cells

Aging and Chronic Respiratory Diseases: Novel Mechanisms

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