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Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma 

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Presentation on theme: "Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma "— Presentation transcript:

1 Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma  Michel Aubier, MD, Gabriel Thabut, MD, PhD, Fatima Hamidi, MSc, Noëlline Guillou, MSc, Julien Brard, MSc, Marie-Christine Dombret, MD, Keren Borensztajn, PhD, Brahim Aitilalne, MSc, Isabelle Poirier, BNBP, Pascale Roland-Nicaise, PharmD, PhD, Camille Taillé, MD, PhD, Marina Pretolani, PharmD, PhD  Journal of Allergy and Clinical Immunology  Volume 138, Issue 3, Pages e11 (September 2016) DOI: /j.jaci Copyright © Terms and Conditions

2 Fig 1 ASM area in control subjects and asthmatic patients. A, ASM area (expressed as the proportion of ASM area over the total biopsy area) was determined by using morphometry and image analysis on α-actin–stained bronchial biopsy specimens from 12 healthy volunteers, 24 patients with mild-to-moderate asthma, and 105 patients with severe asthma. This latter patient group was also analyzed across ASM quartiles. Horizontal bars inside boxes represent median values, and vertical bars represent 25% to 75% interquartile ranges. Overall comparison was made with the Kruskal-Wallis test (P = .0002). *P < .05 compared with control subjects, †P < .05 compared with patients with mild-to-moderate asthma, ‡P < .05 compared with patients with severe asthma of ASM Q1, and §P < .05 compared with patients with severe asthma of ASM Q2 (Mann-Whitney U test). B-D, Representative immunostaining for α-actin (red deposit) in a control subject (Fig 1, B), a patient with mild-to-moderate asthma (Fig 1, C), and 4 patients with severe asthma in ASM Q1, Q2, Q3, and Q4 (Fig 1, D). Original magnification ×40. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

3 Fig 2 Changes in ASM-associated PAR-2 expression in control subjects and asthmatic patients. A, Proportion of ASM area stained for PAR-2 in control subjects (n = 12), patients with mild-to-moderate asthma (n = 24), and patients with severe asthma (n = 105) and in the 105 patients with severe asthma analyzed across ASM quartiles. Data are presented as means ± SEMs, and overall comparisons were made by using the Kruskal-Wallis test (P < .0001). *P < .05 compared with control subjects, †P < .05 compared with patients with mild-to-moderate asthma, and †P < .05 and ‡P < .05 compared with ASM Q1 (Mann-Whitney U test). B-J, Exemplary PAR-2 immunostaining in sections from bronchial biopsy specimens of a patient with mild-to-moderate asthma (Fig 2, B-D) and patients with severe asthma in ASM Q3 with a score of 1+ (Fig 2, E-G) and in ASM Q4 with a score of 3+ (Fig 2, H-J). Fig 2, B, E, and H, indicate PAR-2 immunostaining (red deposit), with high-power inserts in Fig 2, C, F, and I. Fig 2, D, G, and J show the corresponding immunosurface algorithm results (blue = negative, yellow = low intensity, orange = moderate intensity, and red = high intensity). Original magnification ×40 (Fig 2, B, E, and H) and ×400 (Fig 2, C, D, E-G, I, and J). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

4 Fig 3 ASM-associated PAR-2 expression in control subjects and asthmatic patients. Comparison of PAR-2 expression in the ASM of control subjects, patients with mild-to-moderate asthma, and patients with severe asthma (A-D) and of patients with severe asthma, either considered as a whole population or classified according to ASM quartiles (E-H). The intensity of PAR-2 immunostaining was quantified by using an immunosurface algorithm that defined 4 categories of magnitude of expression (ie, absence = score 0 [Fig 3, A and E], low = score 1+ [Fig 3, B and F], moderate = score 2+ [Fig 3, C and G], and high = score 3+ [Fig 3, D and H]). Patients with severe asthma had a lower proportion of ASM area negative for PAR-2 immunostaining than patients with mild-to-moderate asthma and control subjects (Fig 3, A). In addition, the proportion of patients with severe asthma with no or low (score 1+) PAR-2 expression gradually decreased across the ASM quartiles (Fig 3, E and F), whereas the rate of patients with middle and high PAR-2 expression (scores 2+ and 3+) progressively increased (Fig 3, G and H). Patients with severe asthma in ASM Q4 had the highest proportion of ASM area with increased intensity of PAR-2 expression (Fig 3, H). Data are presented as means ± SEMs, and overall comparisons were made by using the Kruskal-Wallis test (P = .027 for Fig 3, A; P = .342 for Fig 3, B; P < .0001 for Fig 3, C; P < .0001 for Fig 3, D; P = .01 for Fig 3, E; P = .001 for Fig 3, F; P = .0083 for Fig 3, G; and P < .0001 for Fig 3, H). *P < .05 compared with control subjects, †P < .05 compared with patients with mild-to-moderate asthma (Fig 3, A-D). *P < .05 compared with Q1, †P < .05 compared with Q2, and ‡P < .05 compared with Q3 in Fig 3, E-H (Mann-Whitney U tests). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

5 Fig 4 BAL fluid levels of PAR-2 ligands in control subjects and asthmatic patients. Scatter plot analyses showing individual levels of tryptase (A), trypsin (B), TF (C), and KLK14 (D) in BAL fluid of control subjects, patients with mild-to-moderate asthma, and patients with severe asthma classified according to ASM quartiles are shown. Horizontal bars indicate median values, and vertical bars denote 25% to 75% interquartile ranges. Overall P values were in Fig 4, A; .54 in Fig 4, B; .05 in Fig 4, C; and .04 in Fig 4, D (Kruskal-Wallis test). *P < .05 compared with control subjects, †P < .05 compared with patients with mild-to-to moderate asthma, ‡P < .05 compared with patients with severe asthma in ASM Q1, and §P < .05 compared with those in ASM Q2 (Mann-Whitney U test). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

6 Fig E1 Assessment of ASM proliferation in bronchial biopsy specimens. Sections from control subjects, patients with mild-to-moderate asthma, and patients with severe asthma were stained with a mouse anti-human PCNA mAb, and the proportion of PCNA+ nuclei over the total number of ASM nuclei was determined by using image analysis. Data are expressed as means ± SEMs. Overall comparison was made with the Kruskal-Wallis test (P = .024), and P values were calculated with the Mann-Whitney U test. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

7 Fig E2 Prevalence of control subjects and asthmatic patients with intramuscular mast cells. Frequency distribution of tryptase-positive (A) and chymase-positive (B) mast cells within the ASM bundles of control subjects, patients with mild-to-moderate asthma, and patients with severe asthma. Patients with severe asthma were also distributed into ASM quartiles. P values were calculated by using the Fisher exact test (2-tailed). No intramuscular mast cells were found in control subjects. Data are presented as means ± SEMs. *P < .05 in relation to patients with mild-to-moderate asthma, †P < .05 in relation to patients with severe asthma in ASM Q1, ‡P < .05 in relation to patients with severe asthma in ASM Q2, and §P < .05 in relation to patients with severe asthma in ASM Q3. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

8 Fig E3 Prevalence of control subjects and asthmatic patients with detectable BAL fluid tryptase levels. Frequency distribution of control subjects, patients with mild-to-moderate asthma, and patients with severe asthma and asthmatic patients with BAL fluid levels of tryptase of greater than the lower limit of detection (eg, 1000 ng/mL). Patients with severe asthma were also distributed into ASM quartiles. P values were calculated by using the Fisher exact test (2-tailed). BAL fluid tryptase was undetectable in control subjects. Data are presented as means ± SEMs. *P < .05 in relation to patients with mild-to-moderate asthma, †P < .05 in relation to patients with severe asthma in ASM Q1, ‡P < .05 in relation to patients with severe asthma in ASM Q2, and §P < .05 in relation to patients with severe asthma in ASM Q3. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © Terms and Conditions

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