ATS 2017

  • Aanvrager: De heer P. Prabhala

American Thorax Society and young investigators meeting, Washington DC and Philidelphia, USA May 16th - May 24th, 2017

Potential role for an imbalance between airway smooth muscle laminin a4 and a5 expression in asthma.

P. Prabhala1,5,6, D.B. Wright1,5,6, C. Bitter1,5,6, P. Robbe1,5,6, T. Pera7, B. Hinz8, G. Kim8, N.H.T. ten Hacken2,5, M. van den Berge2,5, W. Timens3,5, H. Meurs1,5,6, B.G.J. Dekkers1,4,5,6
1Department of Molecular Pharmacology, University of Groningen, Department of Pulmonology University Medical Center Groningen, University of Groningen, 3Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 4Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 5Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen and 6Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands, 7Center for Translational Medicine, Thomas Jerfferson University, Philadelphia, PA, USA 8Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, ON, Toronto, Canada.

Asthma is a chronic inflammatory disease of the airways with hallmarks of reversible airway obstruction, airway hyperresponsiveness (AHR) and remodeling. Airway remodeling is characterized by structural changes, including altered extracellular matrix deposition and increased airway smooth muscle (ASM) mass and contractility, which can contribute to AHR and a decline in lung function. Laminins represent a critical component of the basement membranes underlying the epithelial and endothelial layers and surrounding ASM cells. Using laminin a4 and a5 deficient human ASM cells, we have recently demonstrated that endogenous laminin a4 promotes a contractile and fibrotic ASM phenotype, whereas laminin a5 suppresses the contractile phenotype. In the present study, we investigated the potential clinical relevance of these findings, by measuring ASM laminin a4 and a5 expression in airway wall biopsies of asthmatic patients in relation to lung function and asthma severity.

20 healthy and 32 asthmatic human biopsy sections were stained with laminin a4 and laminin a5 antibodies. Qualitative and semi-quantitative analysis was then performed on the scans of the biopsy sections. The staining intensity of each section was scored three times by two independent investigators in a blinded manner. These scores were then correlated with asthma severity relating to lung function (FEV1).

Significant differences in laminin intensity were found within the ASM layer of sections from control subjects and patients with mild, moderate and severe asthma. ASM laminin a4 intensity was significantly reduced in mild asthmatics when compared to healthy control subjects. Interestingly this reduction was significantly reversed in patients with severe asthma with laminin a4 levels slightly exceeding the control levels. Similar to laminin a4, laminin a5 intensity in the ASM layer was reduced in mild asthmatics, however unlike laminin a4 intensity, the laminin a5 intensity remained attenuated in the moderate and severe patient groups. Consequently we found that the ratio of laminin a4 to laminin a5 gradually increased with the severity of asthma with a significant increase noted between control subjects and patients with severe asthma. In addition we also observed a significant correlation between a reduction in lung function (FEV1) and intensity of laminin a4 present in the ASM of asthmatics.

Our findings suggest that an imbalance in laminin a4 and laminin a5 expression in ASM of asthmatic patients contributes to reduced lung function and more severe asthma, which is in line with our previous observations in laminin a4 and a5 deficient ASM cell cultures.