Bronchial cytokines and growth factors augment fibroblast-induced airway remodeling in adult asthmatics

Abstract

There is abundant evidence implicating the role of the bronchial fibroblast as a key orchestrating cell type in airway remodeling, which has been described in many asthmatics. However, it is not yet understood whether its role in this phenomenon involves alterations in fibroblast phenotypic expression, increased fibroblast numbers, increased collagen synthesis, decreased collagen breakdown, or a combination thereof. Of primary interest and concern in the presented studies were the potential contributions that specific cytokines and growth factors, elaborated in the asthmatic airway, may have in modulating fibroblast-induced airway remodeling activities. Airway remodeling may lead to a state of fixed, or irreversible, airway obstruction, as well as an enhanced airway hyperresponsiveness, despite appropriate and aggressive anti-inflammatory therapy. Given the progressive nature of airway remodeling, the knowledge to be gained from research of this nature is of utmost importance, as an enhanced understanding of the mechanisms driving this phenomenon may facilitate the development of more accurately targeted treatments. Improved treatment modalities could potentially prevent, or perhaps even reverse, the clinical sequelae of airway remodeling.

The objective of the research studies presented was to explore the role of the bronchial fibroblast in airway remodeling with respect to cell proliferation, collagen production, receptor expression, and ultimately fibroblast phenotypic expression. The hypothesis was that specific cytokines and growth factors, important in the asthma phenotype, alter bronchial fibroblast-induced airway remodeling activities, thereby contributing to airway remodeling. By studying airway biopsy tissue obtained from wellcharacterized subjects with and without asthma, many aspects of the disease phenotype that are difficult to account for in alternative experimental models of asthma were not of concern, thus enabling a more focused and precise investigation of fibroblast biology within the context of asthma.

The exposure of bronchial fibroblasts to interleukins 4 and 13, and dexamethasone, each alone and in combination, resulted in enhanced proliferation in mild/moderate asthmatics, as compared to severe asthmatics and normal controls.

The studies presented are suggestive of potentially heterogeneous fibroblast populations as well as asthmatic populations, that are perhaps as of yet uncharacterized. It is conceivable that the asthmatics in these studies, as well as the fibroblasts derived from Stimulation with platelet-derived growth factor isoform BB resulted in significant procollagen production in fibroblasts from severe asthmatics, compared to mild/moderate asthmatics and normal controls, while having no significant effect on proliferation. Conversely, cysteinyl leukotrienes and insulin-like growth factor-I, each alone and in combination, had no effects on fibroblast proliferation or collagen synthesis that differentiated asthmatic populations from each other or from healthy controls. Finally, eosinophil-derived proteins did not affect fibroblast proliferation or procollagen synthesis in any discemable manner that is informative as to the responsiveness of fibroblasts from asthmatics from those of non-asthmatic controls.

The studies presented are suggestive of potentially heterogeneous fibroblast populations as well as asthmatic populations, that are perhaps as of yet uncharacterized. It is conceivable that the asthmatics in these studies, as well as the fibroblasts derived from their airways, may constitute significant subpopulations in addition to those already defined based on their clinical disease. The existence of such subpopulations may account for the differences in fibroblast responsiveness among the asthmatic populations to the various types of cytokines and growth factors investigated in these studies.