Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease

Lamas et al. Respiratory Research (2016) 17:123 DOI 10.1186/s12931-016-0442-4 LETTER TO THE EDITOR Open Access Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease Adelaida Lamas1, Jamie Marshburn2, Vandy P. Stober2, Scott H. Donaldson3 and Stavros Garantziotis2,4* Abstract Cystic fibrosis (CF) is a chronic inflammatory disease that is affecting thousands of patients worldwide. Adjuvant anti-inflammatory treatment is an important component of cystic fibrosis treatment, and has shown promise in preserving lung function and prolonging life expectancy. Inhaled high molecular weight hyaluronan (HMW-HA) is reported to improve tolerability of hypertonic saline and thus increase compliance, and has been approved in some European countries for use as an adjunct to hypertonic saline treatment in cystic fibrosis. However, there are theoretical concerns that HMW-HA breakdown products may be pro-inflammatory. In this clinical pilot study we show that sputum cytokines in CF patients receiving HMW-HA are not increased, and therefore HMW-HA does not appear to adversely affect inflammatory status in CF airways. Keywords: Cystic fibrosis, Hyaluronan, Airway inflammation, Induced sputum Introduction Dear Editor, Cystic fibrosis is a chronic inflammatory disease that is affecting thousands of patients worldwide. Although specific therapies like ivacaftor and lumacaftor/ivacaftor have been approved, they have high costs and are not indicated for all CF patients. Adjuvant anti-inflammatory treatment is an important component of cystic fibrosis treatment, and has shown promise in preserving lung function and prolonging life expectancy [1]. Airway inflammation generates short-fragment HA (sHA, MW 0.1-0.3 × 106 Da) via degradation of structural high molecular hyaluronan (HMW-HA, MW > 106 Da) or de novo expression, and further promotes inflammation and airway hyperresponsiveness. HMW-HA antagonizes sHA effects and has been studied therapeutically in animal models of inflammatory airway disease, such as asthma [2] and cystic fibrosis [3]. In addition, HMW-HA has been recently approved in some European countries for use in upper airway disease, and as an adjunct to hypertonic saline treatment in cystic fibrosis. Inhaled HMW-HA is reported to improve tolerability of hypertonic saline and * Correspondence: 2 Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA 4 National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC 27709, USA Full list of author information is available at the end of the article thus increase compliance [4, 5]. Because HMW-HA ameliorates airway inflammation and hyperresponsiveness, its use in inflammatory lung disease has been advocated. However, a major concern clouding the therapeutic use of inhaled HMW-HA in inflammatory airway disease is that it may itself be degraded to sHA and thus contribute to inflammation. We, therefore, evaluated how chronic use of inhaled HMW-HA affects inflammatory cytokines in induced sputum of cystic fibrosis patients. Methods We compared patients who were converted from treatment with hypertonic saline (HTS) to HTS with 0.1 % HMWHA (MW 0.3-0.5 × 106 Da, brand name Hyaneb®) because they could not tolerate the HTS solution. We performed two comparisons: 1) paired analysis in repeat sputa from patients before, and 4–6 weeks after conversion from HTS to HTS + HMW-HA; and 2) comparison of one group of patients on HTS with another group on HTS + HMW-HA. Patients were children and young adults with CF (11 male and 2 female, age (average ± SD) 15.6 ± 4.7) (Table 1). Results Lung function did not change before and after conversion in comparison 1 (FEV1/FVC pre 95.8 ± 11, FEV1/FVC post 97.1 ± 10.9), and was not different between groups in comparison 2. HMW-HA treatment did not increase induced © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lamas et al. Respiratory Research (2016) 17:123 Page 2 of 4 Table 1 Lung function and clinical characteristics of patients transitioned from HTS to HTS_HMW-HA. Lung function values are expressed as % predicted Patient FEV1/FEV P. aerug. pre post gender age pre post inh Abx AZT BD inh CS dorn α 1 104 103 m 9 + - TOBI + + + + 2 101 104 m 19 - - colistin + + + - 3 95 85 f 13 - - TOBI + - - - 4 96 94 m 19 + + TOBI, colistin + + + - 5 113 113 m 18 - - - - + - - 6 102 104 m 8 - - - - - - - 7 87 102 m 16 + + TOBI - - - + 8 69 76 m 23 + + TOBI - - - + 9 104 104 m 23 + + TOBI, aztreonam + - - + 10 97 97 m 12 - - - - + + + 11 97 105 m 14 - - colistin + - - - 12 97 95 f 14 - - colistin, aztreonam + + + + 13 83 80 m 15 - - - - + + - avg 95.8 97.1 15.6 SD 11.0 10.9 4.7 p 0.57 Abbreviations: avg average value, SD standard deviation, TOBI inhaled tobramycin, Abx antibiotics, AZT azithromycin, BD chronic bronchodilator treatment, CS corticosteroids, p significance value in Wilcoxon matched-pairs, signed-rank test sputum cytokine levels or HA levels in a significant manner (in paired comparisons average ± SD, pre vs post: IL-1β: 369 ± 794 vs 511 ± 1093 pg/ml; IL-6: 1.003 ± 1.775 vs 1.528 ± 1.968 ng/ml; IL-10: 1.140 ± 0.867 vs 1.225 ± 0.988 ng/ml; GM-CSF: 4.759 ± 4.452 vs 4.065 ± 3.342 ng/ml; TNF-α: 5.115 ± 6.477 vs 6.178 ± 10.76 ng/ml; not shown for between-groups comparison). There was large variability in sputum HA levels (range 0.2–2081 ng/ml for pre-HMWHA, 0.2-1070 ng/ml for post-HMW-HA, mean and median 396 and 39.9 ng/ml for pre-HMW-HA, 163.7 and 85.3 ng/ ml for post-HMW-HA). Interestingly, in patients with low initial HA levels in induced sputum, HTS + HMW-HA treatment led to a statistically significant increase in sputum HA levels. On the contrary, in patients with initially high sputum HA levels, initiation of inhaled HMW-HA led to no further increase, and perhaps a trend towards decreased HA levels. Initiation of HMW-HA treatment was reflected in an increase of HMW-HA in induced sputum (Fig. 1). Discussion There are several potential reasons explaining why inhaled HMW-HA does not lead to increased inflammation in this population. First, even though there was apparent degradation of inhaled HMW-HA, there were still appreciable amounts (...truncated)