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

Sarah Rank Rønnow; Jannie Marie Bülow Sand; Line Mærsk Staunstrup; Thomas Bahmer; Michael Wegmann; Lars Lunding; Janette Burgess; Klaus Rabe; Grith Lykke Sorensen; Oliver Fuchs; Erika V Mutius; Gesine Hansen; Matthias Volkmar Kopp; Morten Karsdal; Diana Julie Leeming; Markus Weckmann; ALLIANCE Study Group as part of the German Center of Lung Research (DZL)

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

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

Authors

Sarah Rank Rønnow¹, Jannie Marie Bülow Sand², Line Mærsk Staunstrup^{2

3}, Thomas Bahmer^{4

5}, Michael Wegmann^{4

6}, Lars Lunding^{4

6}, Janette Burgess⁷, Klaus Rabe^{4

5}, Grith Lykke Sorensen⁸, Oliver Fuchs⁹, Erika V Mutius^{10

11}, Gesine Hansen^{12

13}, Matthias Volkmar Kopp^{5

14}, Morten Karsdal², Diana Julie Leeming², Markus Weckmann^{6

14}; ALLIANCE Study Group as part of the German Center of Lung Research (DZL)

Affiliations

¹ Nordic Bioscience A/S, Herlev, Denmark. sar@nordicbio.com.
² Nordic Bioscience A/S, Herlev, Denmark.
³ University of Southern Denmark, The Faculty of Health Science, Odense, Denmark.
⁴ University of Copenhagen, Health, Copenhagen, Denmark.
⁵ LungenClinic Grosshansdorf GmbH, Großhansdorf, Germany.
⁶ Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
⁷ Division of Asthma Mouse Model, Priority Area Asthma & Allergy, Leibniz-Center for Medicine and Biosciences Borstel, Borstel, Germany.
⁸ Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center, Groningen, The Netherlands.
⁹ University Childrens Hospital, Inselspital Bern, Bern, Switzerland.
¹⁰ Dr. von Hauner Children's Hospital, University Hospital Munich, Munich, Germany.
¹¹ Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany.
¹² University Childrens Hospital, Department of Pediatric Pneumology, Allergology and Neonatology Hannover Medical School, Hannover, Germany.
¹³ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany.
¹⁴ Division of Pediatric Pneumology and Allergology, University Medical Center Schleswig-Holstein, Campus Centrum Lübeck, Lübeck, Germany.

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 ).

Associated data

ClinicalTrials.gov/NCT02419274

Grants and funding

Danish Agency for Science and Higher Education/Danish Agency for Science and Higher Education