Assessing arthritis in the context of cystic fibrosis

Clarke, E.A.; Watson, Pippa; Freeston, Jane; Peckham, Daniel; Jones, Andrew M.; Horsley, Alex

doi:10.1002/ppul.24290

Cited by 13 publications

(15 citation statements)

References 38 publications

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“…M1 macrophages from CF patients undergo metabolic reprogramming, through the IRE1α-XBP1 pathway, leading to high mitochondrial and glycolytic activity, with associated increased levels of TNF and IL-6. These findings help to explain why patients with CF suffer from chronic and unresolved inflammation, not only present in the lungs but also in joints, pancreas and gut (32–36). Malfunctioning of the CFTR, along with accumulation of the misfolded channel, in the case of ΔF508 homozygous patients, induces a perpetual chronic low-grade inflammation in CF macrophages, predisposing these cells to a hyper-inflammatory and metabolic response, driven by XBP1s, which is exacerbated by the activation of TLR4 (Figure 7) and may be unresolved due to the lack of M2 macrophage polarization.…”

Section: Discussionmentioning

confidence: 88%

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation

et al. 2019

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Cystic Fibrosis (CF) is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR mutations cause dysregulation of channel function with intracellular accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, with activation of the IRE1α-XBP1 pathway that regulates a subset of unfolded protein response (UPR) genes. This pathway regulates a group of genes that control proinflammatory and metabolic responses in different immune cells; however, the metabolic state of immune cells and the role of this pathway in CF remain elusive. Our results indicate that only innate immune cells from CF patients present increased levels of ER stress, mainly affecting neutrophils, monocytes, and macrophages. An overactive IRE1α-XBP1 pathway reprograms CF M1 macrophages toward an increased metabolic state, with increased glycolytic rates and mitochondrial function, associated with exaggerated production of TNF and IL-6. This hyper-metabolic state, seen in CF macrophages, is reversed by inhibiting the RNase domain of IRE1α, thereby decreasing the increased glycolic rates, mitochondrial function and inflammation. Altogether, our results indicate that innate immune cells from CF patients are primarily affected by ER stress. Moreover, the IRE1α-XBP1 pathway of the UPR is responsible for the hyper-metabolic state seen in CF macrophages, which is associated with the exaggerated inflammatory response. Modulating ER stress, metabolism and inflammation, by targeting IRE1α, may improve the metabolic fitness of macrophages, and other immune cells in CF and other immune-related disorders.

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Section: Discussionmentioning

confidence: 88%

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation

et al. 2019

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“…II. Chronic pain in CF patients is well documented [55], being sometimes present as a side effect of CF therapies, as reported during use of fluoroquinolones and/or azole antifungal agents [56] and even Trikafta [17]. On the other hand, long term use of nonsteroidal anti-inflammatory drugs raises concern due to their renal toxicity, which may be increased in CF patients by the concomitant use of aminoglycosides.…”

Section: Discussionmentioning

confidence: 99%

In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library

Orro

Uggeri

Rusnati

et al. 2021

European Journal of Medicinal Chemistry

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Computational drug repositioning is of growing interest to academia and industry, for its ability to rapidly screen a huge number of candidates in silico (exploiting comprehensive drug datasets) together with reduced development cost and time. The potential of drug repositioning has not been fully evaluated yet for cystic fibrosis (CF), a disease mainly caused by deletion of Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. F508del-CFTR is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. CF is still a fatal disease. Nowadays, it is treatable by some CFTR-rescuing drugs, but new-generation drugs with stronger therapeutic benefits and fewer side effects are still awaited. In this manuscript we report about the results of a pilot computational drug repositioning screening in search of F508del-CFTR-targeted drugs performed on AIFA library by means of a dedicated computational pipeline and surface plasmon resonance binding assay to experimentally validate the computational findings.

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“…En general se observa en pacientes con FQ severa. (150) Hay que recordar que el ciprofloxacino puede causar tendinopatía tanto en niños como adultos con fibrosis quística. (151,152) Insuficiencia renal: Los pacientes con fibrosis quística están en riesgo de presentar insuficiencia renal aguda y daño crónico.…”

Section: Otras Manifestaciones En Fibrosis Quísticaunclassified

Consenso Chileno Para La Atención Integral De Niños Y Adultos Con Fibrosis Quística

C¹,

T.²,

Y³

et al. 2020

Neumol Pediatr

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La Fibrosis Quística (FQ) es la enfermedad hereditaria de pronóstico reservado más frecuente en raza blanca. Desde el año 2003, Chile inicia un Programa Nacional de Fibrosis Quística, de carácter integral, dirigido por la Unidad de Salud Respiratoria del Ministerio de Salud. Hasta la fecha, los principales resultados del Programa registran una significativa mayor sobrevida (promedio 27 años) y una significativa reducción en la edad de diagnóstico de los pacientes ingresados desde 2006 en adelante. El acceso a la canasta GES (Garantías Explícitas en Salud), la implementación del tamizaje neonatal en algunas regiones del país, la organización y la constitución de equipos entrenados en FQ de diversas especialidades, ha contribuido a mejorar los resultados. Si bien las principales manifestaciones son del aparato respiratorio y digestivo, el carácter multisistémico de la FQ obliga a conocer los distintos aspectos involucrados en su manejo, a fin de optimizar los resultados del tratamiento y los recursos invertidos, tanto en el sector público como privado. Este documento es una revisión y actualización sobre los principales aspectos del diagnóstico, seguimiento y tratamiento de las manifestaciones respiratorias y no respiratorias de la FQ.

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Assessing arthritis in the context of cystic fibrosis

Cited by 13 publications

References 38 publications

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation

In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library

Consenso Chileno Para La Atención Integral De Niños Y Adultos Con Fibrosis Quística

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