Microfibrillar‐associated protein 4 in serum is associated with asthma in Danish adolescents and young adults

Abstract

Background Microfibrillar‐associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen‐related protein superfamily, which plays multifaceted roles in innate immunity and normal endothelial function. It has been proposed that MFAP4 promotes the development of asthma in vivo and proasthmatic pathways of bronchial smooth muscle cells in vitro. The aim of this study was to investigate the significance of serum MFAP4 in adolescents and young adolescents with persistent asthma. Methods Prospective, observational study including adolescents and young adults (age 11‐27 years) previously diagnosed with asthma during childhood 2003 to 2005 (0‐15 years) at the four pediatric outpatient clinics in the Region of Southern Denmark (n = 449). Healthy controls were recruited at follow‐up (n = 314). Detection of serum MFAP4 was performed by AlphaLISA technique. Results Current asthma was associated to a 14% higher mean level of serum MFAP4 compared with controls (expβ 1.14, 95% confidence intervals [CI], 1.05‐1.23) and a 6% higher mean level compared with subjects with no current asthma (expβ 1.06, 95% CI, 0.99‐1.13). No association was found at follow‐up between serum MFAP4 and self‐reported atopic symptoms (other than asthma), Asthma Control Test‐score, fractional exhaled nitric oxide (FeNO), nor to flow rate at 1 second, forced vital capacity, and forced expiratory flow 25% to 75%, response to short‐acting beta 2 agonist or mannitol. Conclusions We found a significantly higher mean level of serum MFAP4 in adolescent and young adults with mild to moderate asthma compared with healthy controls but no association to FeNO and lung function nor to the response to short‐acting beta 2 agonist or mannitol. The result supports the hypothesis that MFAP4 plays a role in the pathogenesis of asthma although the marker did not demonstrate any obvious potential as an asthma biomarker in adolescents and young adults with asthma. To understand the possible proasthmatic functions of MFAP4, further investigation in specific asthma phenotypes and the underlying molecular mechanisms is warranted.

MFAP4-Mediated Effects in Elastic Fiber Homeostasis, Integrin Signaling and Cancer, and Its Role in Teleost Fish

“…Furthermore, MFAP4 was upregulated in human bronchial SMCs isolated from asthmatics and promoted both asthmatic bronchial SMC proliferation and their expression of eosinophil chemoattractant CCL11 in an integrin αvβ5dependent manner [80]. Strengthening these observations, circulating MFAP4 was also shown to be mildly upregulated in asthmatic adolescents and young adults [81]. Overall, the deleterious functions of MFAP4 in pathology seem to be uniformly mediated through interaction with RGD-dependent integrins and activation of related downstream signaling.…”

“…While circulatory MFAP4 is recognized to vary moderately with cardiovascular disease and mortality and slightly with asthma [81][82][83], it is markedly increased in liver fibrosis and cirrhosis. MFAP4 was identified amongst the highest regulated proteins in cirrhotic septae by proteomic analysis [62].…”

Association of serum surfactant protein D and SFTPD gene variants with asthma in Danish children, adolescents, and young adults

“…Prospective follow‐up including 449 adolescents and young adults (11–27 years) from a closed cohort of children diagnosed with asthma during 2003–2005 (0–16 years) at all four pediatric outpatient clinics in the Region of Southern Denmark. 23 At follow‐up during 2016–2017, an additional 314 healthy controls with no medical history of asthma or use of asthma medication, and within the same age range were recruited. Controls were recruited through a notice on the digital learning systems from the same schools as the origin of cases.…”

“…Baseline data were obtained from a structured database and biobank established prospectively during the baseline examination as previously described 23 . The data were collected prospectively and consecutively by the treating staff and included a structured questionnaire‐based interview (regarding predisposition, medical history, medication use, and environmental exposures), clinical examination by a pediatrician, blood sampling, skin prick test, spirometry with bronchodilator test and exercise test where appropriate.…”

Circadian, Week-to-Week, and Physical Exercise-Induced Variation of Serum Microfibrillar-Associated Protein 4

“…1 These levels of soluble MFAP4 are likely to partly represent turnover of ECM. However, the level of serum MFAP4 also varies with sex, age and smoking, 18 and is moderately affected by the presence of stable atherosclerosis, 1 peripheral artery disease, 19 presence of abdominal aorta aneurysms, 20 asthma, 21 and chronic obstructive lung disease 22 in addition to more markedly induced levels in liver fibrosis/cirrhosis. 11,[23][24][25][26] Considering sMFAP4 as a biomarker for chronic fibrosing disease warrants detailed evaluation of both technical and normal physiological variation.…”