Fibulin-1 Is Increased in Asthma – A Novel Mediator of Airway Remodeling?

Abstract

BackgroundThe extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma. However, the expression and function of fibulin-1, a secreted glycoprotein which interacts with fibronectin, has not been reported. Fibulin-1 is widely expressed in basement membranes in many organs including the lung. There are four isoforms in humans (A–D) of which fibulin-1C and 1D predominate. The objective of this study was to study the expression of fibulin-1 in volunteers with and without asthma, and to examine its function in vitro.Methodology/Principal FindingsWe used immunohistochemistry and dot-blots to examine fibulin-1 levels in bronchial biopsies, bronchoalveolar lavage fluid and serum. Real-time PCR for fibulin-1C and 1D, and ELISA and western blotting for fibulin-1 were used to study the levels in airway smooth muscle cells. The function of fibulin-1C was determined by assessing its role, using an antisense oligonucleotide, in cell proliferation, migration and wound healing. A murine model of airway hyperresponsiveness (AHR) was used to explore the biological significance of fibulin-1. Levels of fibulin-1 were significantly increased in the serum and bronchoalveolar lavage fluid of 21 asthmatics compared with 11 healthy volunteers. In addition fibulin-1 was increased in asthma derived airway smooth muscle cells and fibulin-1C contributed to the enhanced proliferation and wound repair in these cells. These features were reversed when fibulin-1C was suppressed using an antisense oligomer. In a mouse model of AHR, treatment with an AO inhibited the development of AHR to methacholine.ConclusionsOur data collectively suggest fibulin-1C may be worthy of further investigation as a target for airway remodeling in asthma.

Aortic Valve Stenosis and Atrial Fibrillation Influence Plasma Fibulin-1 Levels in Patients Treated with Coronary Bypass Surgery

“…A possible explanation may be that fibulin-1 is expressed as part of the fibrotic process, and patients with AS or AF have more myocardial fibrosis than patients without. This is supported by the fact that patients with AS and AF had a larger LA and a more hypertrophic LV, and recent studies indicated that fibulin-1 is expressed in the context of tissue fibrosis [10,11]. AS is characterized by a gradual narrowing of the aortic valve which leads to pressure overload of the left ventricle and, as a result of this, increased wall thickness and hypertrophy [12].…”

Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

“…9 It is widely accepted in the literature that there are similarities between the development of fi brosis and embryonic morphogenesis, 10 concepts not limited to the lung. 11 Fibulin-1 is produced by lung fi broblasts 12 and has been shown to play a role in the pathophysiology of patients with asthma, 13 a disease characterized in part by airway fi brosis. 14 We reasoned that dysregulated fi bulin-1 expression may be involved in lung diseases with more extensive fi brosis as mechanisms of fi brogenesis are likely to be shared.…”

Role of YKL-40 in Bronchial Smooth Muscle Remodeling in Asthma

“…We assessed cell migration of BSM cells against YKL-40 using modified Boyden chamber method and wound healing assay, as described previously (21)(22)(23). Actin reorganization was assessed using phalloidin (24).…”