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. 2022 Apr 13;8(1):2.
doi: 10.1186/s40733-022-00084-6.

A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

Sarah Rank Rønnow  1 , Jannie Marie Bülow Sand  2 , Line Mærsk Staunstrup  2   3 , Thomas Bahmer  4   5 , Michael Wegmann  4   6 , Lars Lunding  4   6 , Janette Burgess  7 , Klaus Rabe  4   5 , Grith Lykke Sorensen  8 , Oliver Fuchs  9 , Erika V Mutius  10   11 , Gesine Hansen  12   13 , Matthias Volkmar Kopp  5   14 , Morten Karsdal  2 , Diana Julie Leeming  2 , Markus Weckmann  6   14 ; ALLIANCE Study Group as part of the German Center of Lung Research (DZL)
Affiliations

A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

Sarah Rank Rønnow et al. Asthma Res Pract. .

Abstract

Background: Asthma is a heterogeneous disease; therefore, biomarkers that can assist in the identification of subtypes and direct therapy are highly desirable. Asthma is a chronic inflammatory disease that leads to changes in the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) degradation causing fragments of type I collagen that is released into circulation.

Objective: Here, we asked if MMP-generated type I collagen (C1M) was associated with subtypes of asthma.

Methods: C1M was serologically assessed at baseline in the adult participants of the All Age Asthma study (ALLIANCE) (n = 233), and in The Prospective Epidemiological Risk Factor study (PERF) (n = 283). In addition, C1M was assessed in mice sensitized to ovalbumin (OVA) and challenged with OVA aerosol. C1M was evaluated in mice with and without acute neutrophilic inflammation provoked by poly(cytidylic-inosinic) acid and mice treated with CP17, a peptide inhibiting neutrophil accumulation.

Results: Serum C1M was significantly increased in asthmatics compared to healthy controls (p = 0.0005). We found the increased C1M levels in asthmatics were related to blood neutrophil and body mass index (BMI) in the ALLIANCE cohort, which was validated in the PERF cohort. When patients were stratified into obese (BMI > 30) asthmatics with high neutrophil levels and uncontrolled asthma, this group had a significant increase in C1M compared to normal-weight (BMI < 25) asthmatics with low neutrophil levels and controlled asthma (p = 0.0277). C1M was significantly elevated in OVA mice with acute neutrophilic inflammation compared to controls (P = 0.0002) and decreased in mice treated with an inhibitor of neutrophil infiltration (p = 0.047).

Conclusion & clinical relevance: C1M holds the potential to identify a subtype of asthma that relates to severity, obesity, and high neutrophils. These data suggest that C1M is linked to a subtype of overall inflammation, not only derived from the lung. The link between C1M and neutrophils were further validated in in vivo model.

Trial registration: (ALLIANCE, NCT02419274 ).

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Conflict of interest statement

SRR, JMBS, and DJL are employees and stockholders of Nordic Bioscience A/S; LMS, TB, MW, LL, JB, GLS, and MW declares no conflict of interest; KR declares no conflict of interest, he received grants from Boehringer Ingelheim and personal fees from Antra Zenaca, Novartis, Sanofi, Regeneron, Roche, Chiesi pharmaceuticals outside the submitted work; OF declares no conflict of interest with this publication, he is a consultant for Menarini and Vifor, has received speaker’s fees from Vertex aha! Allergy Centre Switzerland, Menarini, Novartis, ALK and has received travel support from Milupa/Nutricia, Stallergnes Greer and Bencard; EVM declares personal fees from GlaxoSmithKline & Co. KG, Decision Resources Inc., London, Pick Research Solutions, Novartis Pharma GmbH, ALK Scherax Arzneimittel GmbH, Sandler Program for Asthma Research (SPAR), Aptel Research, and Penn Technology Partnership, grants from Airsonett AB, personal fees from American Academy of Allergy Asthma & Immunology, grants from European Commission, grants from German Research Foundation, personal fees from Massachusetts Medical Society, outside the submitted work; In addition, EVM has a patent Publication number EP2361632: with royalties paid to Protectimmun GmbH, a patent Publication number EP 1411977: licensed to Protectimmun GmbH, a patent Publication number EP1637147: licensed to Protectimmun GmbH, and a patent Publication number EP 1964570: licensed to Protectimmun GmbH; GH declares no conflict of interest and is a consultant for Novartis and Sanofi; MVK declares personal fees from Novartis Pharma GmbH, Allergopharma GmbH, ALK Abello, Chiesi GmbH, Infectopharm GmbH, Meda GmbH, and Abbvie GmbH, outside the submitted work; MK is a fulltime employee and stockholder of Nordic Bioscience A/S.

Figures

Fig. 1
Fig. 1
A schematic overview of the procedure in the OVA-induced asthma mouse model. Mice were sensitized to OVA (i.p.) on days 1, 14, and 21 and challenged with OVA aerosol on days 26, 27, and 28 to induce acute allergic airway inflammation. Acute neutrophilic inflammation were provoked by i.t. instillation of the TLR-3 ligand poly(cytidylic-inosinic) acid on day 28. A control group was sham sensitized to PBS and challenged with OVA aerosol. The mice were sacrificed on day 29
Fig. 2
Fig. 2
 A Serum C1M levels were increased in severe asthmatics (n = 86) compared to healthy controls (n = 41) and mild-moderate asthmatics (n = 106) compared to healthy controls (P = 0.0005, P = 0.0075), respectively. Data are presented as a Tukey box plot and analyzed using the Kruskal-Wallis test using Dunn’s multiple comparisons. Asterisks indicate statistically significance: **p < 0.01, ***p < 0.001. B Correlation between serum log-transformed C1M level and airway resistance at 5 Hz. Data were analysed using spearman’s correlation (r = 0.281, p > 0.0001)
Fig. 3
Fig. 3
The relationship between BMI, age, smoking, allergic asthma, FeNO, the use of systemic steroids, inhaled corticosteroid dosage, blood neutrophils, and blood eosinophils on the levels of C1M in asthmatics were tested using a feature ranking using random forest. The top 3 most important attributes to C1M levels in the ALLIANCE cohort is Age, Blood neutrophils, and BMI
Fig. 4
Fig. 4
 A Correlation between serum C1M level and blood neutrophils. Data were analysed using spearman’s correlation (r = 0.273, p < 0.0001). B Patients were stratified into high versus low blood neutrophils levels based on the median. C1M was significantly increased in patients with high neutrophil levels (n = 109) compared to low (n = 82) (p = 0.0154). C C1M was significantly increased in obese (BMI > 30) patients (n = 49) compared to normal-weight (BMI < 25) patients (n = 65) (p = 0.0137). D Obese asthmatics with high blood neutrophils (n = 33) had a significant increase in C1M compared to normal-weight asthmatics with low blood neutrophils (n = 36) (p = 0.0026). Data are presented as a Tukey box plot and analyzed using the Mann-Whitney test. Asterisks indicate statistically significance: *p < 0.05, **p < 0.01
Fig. 5
Fig. 5
 A Serum C1M levels were significantly increased in patients with uncontrolled asthma with a high blood neutrophil level (n = 53) compared to patients with controlled asthma and a low blood neutrophil level (n = 30) (p = 0.0387). B C1M was significantly increased in obese patients with high neutrophil levels and uncontrolled asthma (n = 20) compared to normal-weight patients with low neutrophil levels and controlled asthma (n = 15) (p = 0.0277). Data are presented as a Tukey box plot and analyzed using the Mann-Whitney test. Asterisks indicate statistically significance: *p < 0.05
Fig. 6
Fig. 6
 A Total cell count in the bronchoalveolar lavage (BAL) were significantly increased in OVA mice and acute neutrophilic inflammation compared to control (P < 0.0001, P < 0.0001), respectively B Serum C1M was significantly increased in serum from OVA mice and mice with an acute neutrophilic inflammation as compared to controls (P < 0.0001, P = 0.0002), respectively. C Correlation between serum C1M level and airway resistance (r = 0.501, p = 0.0005). D Correlation between serum C1M level and airway compliance (r = -0.473, P = 0.0016). E Correlation between serum C1M level and BAL neutrophil was not significant. F Serum C1M levels were decreased in OVA mice treated with CP17, a peptide inhibiting neutrophil accumulation, compared to OVA mice treated with a scrambled peptide (p = 0.047). Data are presented as bar graphs and analyzed using the Kruskal-Wallis test using Dunn’s multiple comparisons or the Mann-Whitney test. The correlation was analyzed using spearman’s correlation. Asterisks indicate statistically significance: *p < 0.05, ***p < 0.001 and ****p < 0.0001
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References

    1. Global Asthma Network. The Global Asthma Report 2014. Auckland, New Zeal 2014.
    1. Reddel HK, Bateman ED, Becker A, et al. A summary of the new GINA strategy: A roadmap to asthma control. Eur Respir J. 2015;46:622–39. - PMC - PubMed
    1. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2015.
    1. Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol [Internet] 2010;11(7):577–584. Available from: http://www.nature.com/doifinder/10.1038/ni.1892. - DOI - PMC - PubMed
    1. McGrath KW, Icitovic N, Boushey HA, et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612–9. doi: 10.1164/rccm.201109-1640OC. - DOI - PMC - PubMed

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