? Asthma is a chronic inflammatory disease of the airways, in which viral infection is a known risk factor. It is characterized by pathological changes in the mucosal and submucosal tissues, including the deposition of an extensive hyaluronan-rich extracellular matrix, which contributes to the impairment of normal lung function. The changes in the extracellular matrix have been considered to be a passive, albeit obstructive, consequence of the inflammatory response. However, our in vitro studies with murine airway smooth muscle cells now show that a unique hyaluronan network, synthesized in response to the viral mimic, poly I:C, specifically engages mononuclear leukocytes via a process involving the hyaluronan binding protein, CD44, on the leukocyte surface. After adhesion, the CD44 molecules undergo clustering (capping) on the leukocyte surface, and concurrently, hyaluronan is degraded and internalized by the leukocytes. Sections of lung tissue from an asthmatic patient show a similar hyaluronan meshwork, with embedded leukocytes, including some with capped CD44. Therefore, we propose, that the formation of these unique hyaluronan structures in vivo, in response to airway pathogens, has an instructive role in the retention of the inflammatory cells at the affected site and induces these cells to resorb the extracellular matrix produced during inflammation. The clearance of this pathological hyaluronan-rich matrix by leukocytes is crucial for the successful resolution of airway inflammation.
Our specific aims are to develop and refine the murine airway smooth muscle cell model to determine the mechanisms involved in: (i) the assembly of the hyaluronan structures, (ii) the adhesion of leukocytes to these structures and (iii) the changes in the behavior of leukocytes after their attachment to these structures, including CD44 capping and hyaluronan degradation and internalization. Delineation of these mechanisms will add a new dimension to understanding the role that extracellular matrix can have in recruiting inflammatory cells to the site of a pathogenic assault and may also identify new intervention possibilities to prevent the excessive inflammatory response characteristic of asthmatic flares. ? ?
| Cheng, Georgiana; Swaidani, Shadi; Sharma, Manisha et al. (2011) Hyaluronan deposition and correlation with inflammation in a murine ovalbumin model of asthma. Matrix Biol 30:126-34 |
