Nocturnal exacerbations can be severe and possibly lead to death, therefore understanding their mechanism is critical to the treatment of asthma and likely provides a unique insight into the pathogenesis of this disease. It has been shown that increased airway inflammation at night contributes to airway obstruction in asthma. In addition, circadian variation in epinephrine and cortisol are felt to influence the appearance of nocturnal asthma. What remains to be established is the mechanism by which circadian rhythm promotes enhanced airway inflammation at night. Preliminary data suggest that fibronectin (FN), a multi- functional matrix protein present in airways of asthma patients, is increased in BAL fluid obtained from nocturnal asthma (NA) subjects at 0400. Furthermore, FN levels in BAL fluid obtained at 0400 correlated with the severity of NA. Fibronectin enhances the function of eosinophils (EOS) (e.g. generation of LTC4, release of oxygen radicals and granule proteins), and preliminary data indicate that FN increases eosinophil generation of GM-CSF by stabilizing its coding. Thus, it is hypothesized that a major factor leading to nocturnal asthma is enhanced generation of FN at night, that contributes to the recruitment and activation of EOS through a GM-CSF-mediated mechanism.
The specific aims are to: 1) Establish, in nocturnal asthma, the circadian pattern of circulating and airway FN levels in relation to lung function; plasma epinephrine and cortisol, numbers and activation of airway and blood EOS; 2) Establish whether the levels of GM-CSF mRNA, in BAL and circulating EOS, undergo circadian variation and whether this effect is mediated by FN-induced stabilization of GM-CSF mRNA; and 3) Establish the type, functional activity, cell source and regulation of FN generation by airway cells.
| Esnault, Stephane; Fang, Yulin; Kelly, Elizabeth A B et al. (2007) Circadian changes in granulocyte-macrophage colony-stimulating factor message in circulating eosinophils. Ann Allergy Asthma Immunol 98:75-82 |
| Kelly, E A B; Houtman, J J; Jarjour, N N (2004) Inflammatory changes associated with circadian variation in pulmonary function in subjects with mild asthma. Clin Exp Allergy 34:227-33 |
| Panzer, Sarah E; Dodge, Ann M; Kelly, Elizabeth A B et al. (2003) Circadian variation of sputum inflammatory cells in mild asthma. J Allergy Clin Immunol 111:308-12 |
