According to information appearing in the April issue of The American Journal of Pathology, doctors are gaining new leverage in the fight against lung injury caused by acid reflux. The most familiar symptoms of acid reflux include heartburn and acid regurgitation, but in some patients, acid reflux harms more than the gastrointestinal tract—it also injures the respiratory tract. Acid aspiration into the lungs damages the epithelial barrier and initiates acute inflammation, resulting in asthma exacerbation, chronic cough, and in the most severe cases, acute respiratory distress syndrome (ARDS). Current management involves supportive therapies: airway maintenance, supplemental oxygen, and fluid therapy.
Because treatment of acid-induced lung injury is lacking, investigators are examining how the body heals itself from such insults in the hopes of harnessing the same mechanisms for improved medical therapies. Recently, the cellular inflammatory regulators COX-2 and LXA4 have been identified in the resolution of acid-induced lung injury in a mouse model. To determine further how COX-2 and LXA4 work at the cellular/molecular level, Dr. Bruce Levy and colleagues are exploring the resolution of acid-induced injury of the epithelial barrier of the lungs.
Using a cell culture system that replicates the air-cell interface of the lungs, Levy’s group applied acid directly to the surface of the cell layer, inducing injury and death of the top layer of cells, which were shed within 2 hours. Remarkably, the layer was mostly restored within 6 hours. But how did this restoration occur?
By 2 hours following injury, the researchers found increased expression of COX-2 and the LXA4 receptor (ALX), which relied, in part, on COX-2 derived products, such as prostaglandin E2. LXA4, known to aid resolution of injury in vivo, induced proliferation of basal airway epithelial cells and reduced release of the inflammatory cytokine IL-6 in the culture system. In addition, LXA4 further prevents acute inflammation by blocking experimental transmigration of neutrophils into the damaged region. Combined, these events promote restoration of the damaged layer of cells without the added injury that can occur from excessive neutrophil and epithelial cell inflammatory responses.
These data demonstrate the importance of the anti-inflammatory function of LXA4 and its receptors (ALX) in the respiratory tract’s ability to heal following acid-aspiration-induced lung injury. The capacity to enhance LXA4 signaling therapeutically may allow faster resolution of such lung injury in patients with severe disease, providing a potential new treatment in the struggle against acid-induced lung diseases, including ARDS.
Finally, this new model of acid aspiration lung injury accurately imitates in vivo cell death and shedding as well as recovery, thus providing researchers a means of testing new treatment strategies for hastening resolution of acid-induced damage.