Molecular Imaging of Pulmonary Fibrosis: Another Step Forward.
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ABSTRACT:
SUBMITTER: Montesi SB
PROVIDER: S-EPMC7781130 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC6444631 | biostudies-literature
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| S-EPMC6355490 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis is a progressive scarring disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Recent studies support the hypothesis that these compositional and mechanical changes create a progressive feed-forward loop in which enhanced matrix deposition and tissue stiffening contribute to fibroblast and myofibroblast differentiation and activation, which further perpetuates matrix production and stiffening. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. Although our understanding of mechanotransduction pathways associated with pulmonary fibrosis remains incomplete, recent progress has allowed us to begin to elucidate the specific mechanisms supporting fibrotic feed-forward loops. The mechanosensors discussed here include integrins, Piezo channels, transient receptor potential channels, and nonselective ion channels. Also discussed are downstream transcription factors, including myocardin-related transcription factor and Yes-associated protein/transcriptional coactivator with PDZ-binding motif. This review describes mechanosensors and mechanotransduction pathways associated with fibrosis progression and highlights promising therapeutic insights.
| S-EPMC7768346 | biostudies-literature
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| S-EPMC6835043 | biostudies-literature
Project description:Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis.Objectives: To phenotype patients with IPF for potential targeted therapy, we developed 64Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2+ monocytes and macrophages using positron emission tomography (PET).Methods: CCR2+ cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2+ cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by 64Cu-DOTA-ECL1i PET.Measurements and Main Results: Mouse models established that increased 64Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2+ cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR2+ macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2+ cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones.Conclusions: These findings support a role for imaging CCR2+ cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).
| S-EPMC7781144 | biostudies-literature
Project description:There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with 64Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe 64Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of 64Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of 64Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer. Conclusion:64Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
| S-EPMC6944164 | biostudies-literature
Project description:Osmotic actuation is a ubiquitous plant-inspired actuation strategy that has a very low power consumption but is capable of generating effective movements in a wide variety of environmental conditions. In light of these features, we aimed to develop a novel, low-power-consumption actuator that is capable of generating suitable forces during a characteristic actuation time on the order of a few minutes. Based on the analysis of plant movements and on osmotic actuation modeling, we designed and fabricated a forward osmosis-based actuator with a typical size of 10 mm and a characteristic time of 2-5 minutes. To the best of our knowledge, this is the fastest osmotic actuator developed so far. Moreover, the achieved timescale can be compared to that of a typical plant cell, thanks to the integrated strategy that we pursued by concurrently addressing and solving design and material issues, as paradigmatically explained by the bioinspired approach. Our osmotic actuator produces forces above 20 N, while containing the power consumption (on the order of 1 mW). Furthermore, based on the agreement between model predictions and experimental observations, we also discuss the actuator performance (including power consumption, maximum force, energy density and thermodynamic efficiency) in relation to existing actuation technologies. In light of the achievements of the present study, the proposed osmotic actuator holds potential for effective exploitation in bioinspired robotics systems.
| S-EPMC4097062 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-06-09 | GSE173357 | GEO
Project description:It is well known that high-resolution computed tomography (HRCT) is an essential component of the diagnostic pathway in idiopathic pulmonary fibrosis (IPF). Honeycombing, a common feature of IPF seen on HRCT, is crucial for an accurate diagnosis. Unfortunately, identification of honeycombing is not always straightforward, and there is some disagreement regarding its imaging features. It can be difficult to distinguish honeycombing from traction bronchiectasis and emphysema, although several imaging characteristics can be helpful. Recently, there has been an interest in expanding the use of HRCT beyond diagnosis for disease monitoring and prognostication, and several studies have provided valuable contributions in this regard. Traction bronchiectasis and the extent of fibrosis, for example, have been reported to be powerful prognostic predictors for mortality. Finally, considering the difficulties in diagnosis of "possible usual interstitial pneumonia", clinicians should always be aware that clinical factors must be considered together with HRCT in order to reach an accurate diagnosis and provide appropriate treatment.
| S-EPMC9487568 | biostudies-literature
Project description:In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.
| S-EPMC5674156 | biostudies-literature