Transforming growth factor alpha increases extracellular matrix within the airway smooth muscle layer in a transgenic mouse model of airway disease

Abstract

Increased expression of transforming growth factor alpha (TGF-a) and its receptor, epidermal growth factor receptor, may contribute to the increased thickness of airway smooth muscle (ASM) layer in asthma. Aim: In a transgenic mouse model of increased TGF-a expression, we have examined the number and size of ASM cells and the volume fraction of extracellular matrix (ECM) within the ASM layer. Methods: TGF-α was conditionally expressed in the airway epithelium of transgenic mice by exposure to doxycycline in chow (from 0, 10 and 14 days) which induces deficiency in early growth response-1 which upregulates TGF-a induced airway disease. On formalin fixed transverse airway sections, stained with haematoxylin (30μm), the volume density (N V ) of ASM cell nuclei was estimated using an optical disector (x1000) and the ASM area measured. On contiguous thin (0.5μm) sections (Masson9s trichrome) the volume fraction of ECM (VvECM) was estimated. The mean ASM cell volume (V C = 1/(N V x VvASM)), the number of ASM cells (NL = N V x ASM area x1mm) and volumes of ASM and ECM per mm of airway were calculated. Conclusion: The volume fraction of ECM in the layer of smooth muscle and the average ASM cell size (hypertrophy) are increased in this mouse model, although considerable variablility exists between animals.