Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Corcoran, Timothy E.; Thomas, Kristina; Myerburg, Michael M.; Muthukrishnan, Ashok; Weber, Lawrence; Frizzell, Raymond A.; Pilewski, Joseph M.

doi:10.1183/09031936.00059009

Cited by 18 publications

(17 citation statements)

References 23 publications

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“…In the current study, MCC and DTPA absorption were measured in vivo using dual-isotope ( 99m Tc-SC and 111 In-DTPA) imaging. While statistically significant differences in baseline MCC were not detected between study groups, DTPA absorption was found to be increased in CF patients, consistent with our previous in vivo [11] and in vitro [10] results. These findings were similar in central zone measurements and when data were analysed using the AAC.…”

Section: Discussionsupporting

confidence: 91%

“…Previous in vitro results from our laboratory have shown that the absorption rate of radiolabelled DTPA is: 1) increased in CF HBE cell cultures compared with non-CF cell cultures; 2) well correlated with the ASL absorption rate; and 3) influenced by transepithelial osmotic gradients [10]. In vivo , we have previously shown that the absorptive clearance of DTPA is increased in the lungs of CF subjects compared with healthy volunteers [11]. Taken together, these results support the hypothesis that DTPA absorption correlates with transepithelial liquid absorption.…”

Section: Introductionmentioning

confidence: 97%

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Quantitative imaging of airway liquid absorption in cystic fibrosis

Locke

Myerburg

Markovetz

et al. 2014

European Respiratory Journal

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New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ~50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 97%

Quantitative imaging of airway liquid absorption in cystic fibrosis

Locke

Myerburg

Markovetz

et al. 2014

European Respiratory Journal

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“…Tc-SC is only cleared by MCC while In-DTPA is cleared by both MCC and absorption. Subtracting the MCC clearance rate from the total DTPA clearance rate provides an estimate of the absorptive component of DTPA clearance (ABS) [10, 12, 13]. Studies in epithelial cell cultures have demonstrated proportional relationships between ABS and ASL absorption.…”

Section: Methodsmentioning

confidence: 99%

“…Measurements of mucociliary clearance (MCC) using nuclear imaging techniques are used in CF therapeutics development [5–9]. Our center has developed a variation of this technique that includes a parallel measurement of small molecule absorption (ABS) [10–13]. In vitro studies have demonstrated a proportional relationship between ABS and ASL absorption rate [11].…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung

Locke¹,

Myerburg²,

Weiner³

et al. 2016

Eur Respir J

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Airway surface liquid hyper-absorption and mucus accumulation are key elements of cystic fibrosis (CF) lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance. Our imaging technique utilizes two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult CF subjects. Experimental factors were assessed in 29 adult and pediatric CF subjects (51 scans). Patient factors were assessed in a sub-group with optimal aerosol deposition (37 scans, 24 subjects). Pediatric subjects (n=9) performed initial and 2 year follow-up scans. Control subjects from a previously reported study are included for comparison. High rates of central aerosol deposition influenced measurements of ABS and to a lesser extent MCC. Depressed MCC in CF was only detectable in subjects with previous Pseudomonas aeruginosa (PA) infection. CF subjects without PA had similar MCC to control subjects. CF subjects had consistently higher ABS rates. We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in CF is associated with PA infection. ABS is consistently increased in CF.

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“…Retention of Tc-SC, which is a metric of MCC, is shown with model fit for each patient group in Figure 3 [3]. Data from pediatric patients with CF and healthy controls who inhaled isotonic saline is also shown.…”

Section: Resultsmentioning

confidence: 99%

A Physiologically-Motivated Compartment-Based Model of the Effect of Inhaled Hypertonic Saline on Mucociliary Clearance and Liquid Transport in Cystic Fibrosis

et al. 2014

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BackgroundCystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data.MethodsUsing functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity.ResultsThis model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment.ConclusionsWe postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway.

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Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Cited by 18 publications

References 23 publications

Quantitative imaging of airway liquid absorption in cystic fibrosis

Quantitative imaging of airway liquid absorption in cystic fibrosis

Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung

A Physiologically-Motivated Compartment-Based Model of the Effect of Inhaled Hypertonic Saline on Mucociliary Clearance and Liquid Transport in Cystic Fibrosis

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