Mucociliary Clearance Differs in Mild Asthma by Levels of Type 2 Inflammation

Abstract

Background: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown.

Research question: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids?

Study design and methods: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12).

Results: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts.

Interpretation: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

Keywords: asthma; cilia; lung imaging; mucociliary clearance; mucus; scintigraphy; type 2 inflammation.

Graphical abstract

Figure 1

Breakdown of study screening, group assignment, and reasons for exclusion or not completing the MCC scan. Patients were assigned to the “type 2 low” (T2Lo) group if they had exhaled nitric oxide (Feno) <25 ppm and to the “type 2 high” (T2Hi) group (n = 18) with Feno > 35 ppm. Subjects in the range between groups were excluded.

Figure 2

A, Mucociliary clearance (MCC) in mild asthma subjects grouped as type 2 low (T2Lo) and type 2 high (T2Hi) based on exhaled nitric oxide (Feno) as compared with a historical group of healthy control subjects (HC). B, MCC-adjusted estimates and corrects for the effects of differences in aerosol distribution amongst the subjects based on their central aerosol deposition %. Methodology is included in e-Appendix 1.

Figure 3

Comparing gene expression levels between T2Hi and T2Lo groups based on samples obtained via bronchial brushings. Gene (protein): A, NOS2 (iNOS); B, CCL26 (eotaxin-3); C, POSTN (periostin); D, ALOX15 (arachidonate 15-lipoxygenase). All expression levels presented as the natural log of measured levels. Not depicted: MUC5AC P = .56, SLC26A4 (pendrin) P = .84, FOXJ1(Forkhead box protein J1) P = .88.

Figure 4

Correlations between T2 gene expression patterns and Feno. All expression levels presented as the natural log of measured levels. Correlations by Spearman: gene (protein): A, NOS2 (iNOS) all r = 0.72, P < .0001; T2Hi r = 0.61, P = .03; T2Lo r = 0.06, P = .84. B, CCL26 (eotaxin-3) all r = 0.79, P < .0001; T2Hi r = 0.52, P = .07; T2Lo r = 0.59, P = .02. C, POSTN (periostin) all r = 0.81, P < .0001; T2Hi r = 0.72, P = .005; T2Lo r = 0.75, P = .001. D, ALOX15 all r = 0.66, P = .001; T2Hi r = 0.47, P = .17; T2Lo r = 0.57, P = .04. ● = T2Lo, ♢ = T2Hi. Dashed line = T2Hi linear fit. Solid line = T2Lo linear fit.

Figure 5

Correlations between T2 gene expression patterns, Feno and MCC_adjusted. All expression levels presented as the natural log of measured levels. Correlations by Spearman: gene (protein): A, NOS2 (iNOS) all r = -0.58, P = .001; T2Hi r = -0.06, P = .84; T2Lo r = -0.27, P = .33. B, CCL26 (eotaxin-3) all and r = -0.49, P = .008; T2Hi r = 0.19, P = .54; T2Lo r = -0.23, P = .40. C, POSTN (periostin) all r = -0.43, P = .02; T2Hi r = 0.12, P = .69; T2Lo r = -0.39, P = .14. D, Feno , all r = -0.54, P = .001 (if Feno > 150 ppb removed, r = -0.45, P = .008); T2Hi r = -0.32, P = .19; T2Lo r = -0.10, P = .70. ● = T2Lo, ♢= T2Hi. Solid line is whole group linear fit.