Multi-parametric MRI characterization of inflammation in murine skeletal muscle.
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ABSTRACT:
SUBMITTER: Bryant ND
PROVIDER: S-EPMC4134016 | biostudies-other | 2014 Jun
REPOSITORIES: biostudies-other
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Project description:PurposeQuantitative multi-parametric MRI (mpMRI) methods may allow the assessment of renal injury and function in a sensitive and objective manner. This study aimed to evaluate an array of MRI methods that exploit endogenous contrasts including relaxation rates, pool size ratio (PSR) derived from quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), nuclear Overhauser enhancement (NOE), and apparent diffusion coefficient (ADC) for their sensitivity and specificity in detecting abnormal features associated with kidney disease in a murine model of unilateral ureter obstruction (UUO).MethodsMRI scans were performed in anesthetized C57BL/6N mice 1, 3, or 6 days after UUO at 7T. Paraffin tissue sections were stained with Masson trichrome following MRI.ResultsCompared to contralateral kidneys, the cortices of UUO kidneys showed decreases of relaxation rates R1 and R2 , PSR, NOE, and ADC. No significant changes in CEST effects were observed for the cortical region of UUO kidneys. The MRI parametric changes in renal cortex are related to tubular cell death, tubular atrophy, tubular dilation, urine retention, and interstitial fibrosis in the cortex of UUO kidneys.ConclusionMeasurements of multiple MRI parameters provide comprehensive information about the molecular and cellular changes produced by UUO. Magn Reson Med 79:2216-2227, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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Project description:BACKGROUND:Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. METHODS:We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. RESULTS:Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. CONCLUSIONS:These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.
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Project description:Interventions: Single arm prospective observationaI imaging biomarker study.
Patients will have standard treatment, consisting of neoadjuvant chemoradiotherapy followed by surgery. There will be no change to the patient’s treatment by participating in this study. Patients participating in this study will have multi-parametric MRI and PET/CT at the following 3 time-points:
1. Prior to chemoradiotherapy
2. During the third week of chemoradiotherapy
3. Post chemoradiotherapy, within 1 week prior to surgery.
A multi-parametric MRI incorporates standard morphological as well as diffusion weighted imaging and dynamic contrast enhanced sequences.
The total follow-up duration will be 2 years from date of surgery.
Primary outcome(s): Correlation of multi-parametric MRI (diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE)) at 3 Tesla with surgical histopathology tumour regression grade (TRG).
Histopathological assessment will be performed on surgical specimens. TRG assessment will be performed as per the modified classification of Ryan et al set out in the AJCC Cancer Staging Manual, 7th Edition as follows:
TRG 0 (complete response) - no viable cancer cells
TRG 1 (moderate response) - single cells or small groups of cancer cells
TRG 2 (minimal response) - residual cancer outgrown by fibrosis
TRG 3 (poor response) - minimal or no tumour kill; extensive residual cancer.
[At baseline pre-chemoradiotherapy, week 3 of chemoradiotherapy, and post-chemoradiotherapy (within 1 week prior to surgery) ]
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