Adenosine up‐regulation of the mucin gene, MU2, in asthma

Abstract

Mucus hypersecretion is a hallmark of asthma that contributes to airway obstruction. While the etiology is not well understood, hypersecretion has been linked to the presence of cytokines such as IL-4, IL-5, IL-9, and IL-13 in the inflamed airway. The presence of adenosine has also been noted in asthmatic airways, and adenosine-mediated signaling in mast cells has been implicated in the severe bronchoconstriction and inflammation prevalent in these patients (1, 2). Here we examine the possibility that adenosine also contributes to mucus hypersecretion by airway epithelial cells. Results in cultured airway epithelial cells showed that MUC2 mucin expression increased in response to adenosine. This appeared to be mediated by a pathway initiated at the adenosine A1 receptor that transduced signals through a Ca2+-activated Cl- channel and EGFR. That this signaling cascade is relevant to asthmatic hypersecretion was indicated by results showing that mucin induction by asthmatic tracheal aspirates was reduced by A1, CLCA1, and EGFR inhibitors. These results suggest that adenosine cooperates with inflammatory cytokines to stimulate mucin production in the asthmatic airway and supports the use of A1, CLCA1, and EGFR inhibitors in the treatment of asthma.

A2B Adenosine Receptors Regulate the Mucus Clearance Component of the Lung's Innate Defense System

“…For example, McCoy and coworkers showed that inhibition of A1-R increased cAMP and stimulated a Cl -conductance in immortalized normal and CF cell lines, as well as in CF nasal polyps (39). In addition, McNamara and colleagues found that A 1 -R were present in airway epithelia and that stimulation of these receptors increased intracellular Ca 21 and mucus production (40). We did not detect A1-R by RT-PCR, and we also found no change in Ca 21 i upon ADO-addition.…”

“…We did not detect A1-R by RT-PCR, and we also found no change in Ca 21 i upon ADO-addition. However, McNamara and coworkers used airway cells obtained from Clonetics, Inc. that had been passaged several times to increase cell numbers before culturing, raising the possibility that their phenotype had been changed by the extensive passaging (40). While we cannot exclude the possibility that our HBECs have also begun to change their phenotype during culturing as compared with the native tissue, we cultured our cells immediately after isolation from donor lungs to minimize this eventuality.…”

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…It has also been suggested that adenosine cooperates with inflammatory cytokines to stimulate mucin production in the asthmatic airway (McNamara et al, 2004).…”

Involvement of A1adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

“…A very recent study reported that the expression of A 1 AR is significantly elevated in airway smooth muscle in asthmatic patients (7). Other than the effects on airway smooth muscle, the A 1 AR has been implicated in increased mucin production in human tracheal cells (36) and in mediating monocyte phagocytosis (49). All these studies suggest a strong role for the A 1 AR in asthma, both in airway obstruction and inflammation.…”