The seamless tight-junction epithelial cells that line our respiratory tracts are primed and hair-trigger ready for action in the event of injury. Those lungs, bronchial tubes and other breathing passages are sitting ducks for harm. Airway researcher Paola Vermeer, at the University of Iowa in Iowa City, counts the commonest hazards, "whether that be breathing in cold dry air, cigarette smoking and mechanical injuries such as you may get from a ventilator, viruses - anything that compromises the functioning of the tight junction."
Cell biologist Vermeer, an assistant research scientist, is first author of an article in the current issue of Nature, dated March 20, 2003. Its title: "Segregation of receptor and ligand regulates activation of epithelial growth factor receptor."
"The overall finding of this paper," Vermeer told BioWorld Today, "is that the airway epithelial cells can express at the same time a signaling molecule and its activating receiver molecule, yet keep them separate from each other until they're called upon to be activated. So when there's a mechanical wound in an airway," Vermeer continued, "that's one instance where a signaling molecule would have access to the receiver molecules and allow for their activation. That's important as far as the way we think about respiratory diseases - asthma, chronic bronchitis, cystic fibrosis, chronic obstructive pulmonary disease - where the cellular barrier that would normally keep the signaling molecules separated from the receiver is not functioning normally. It's not really segregating one from the other.
"So abnormal signals get in. And in the person who doesn't have a diseased airway, signals are inhibited from getting through. So it's a different way for us to think about the consequences of what happens in a diseased lung, for example, when that signal is coming through. The whole mechanism is novel," Vermeer observed. "This type of molecular repair has never been described before. What makes it possible," she explained, "is that the epithelial cells themselves are polarized. That is, they have an apical (upper) domain and a basolateral (bottom) domain. So it's not just a round cell where any part is equivalent to another. They're very distinct parts of the cells."
Therapeutic Handles On Asthma, Cystic Fibrosis
"So now that we have a handle on what the players are," Vermeer noted, "we know at least one of the ligands that's present in the airway surface liquid. And we know that it's segregated from its receptor. So now, say, in a disease like asthma, we may be able to go in, and though the junction may not be functioning normally, keep them separated from each other. We can, for example, use neutralizing antibodies to inhibit the effect of the ligand getting down to the basolateral membranes. It may still be able to sneak through and reach that domain, but with antibodies that won't leak activation at the lower membrane.
"And that's important in asthma," Vermeer pointed out, "because an asthmatic's lungs look very different from that of a person who doesn't have asthma. So now that we can inhibit the ligand's effect on the receptor, it may give us new therapeutic approaches.
"Heregulin, for example," Vermeer observed, "which is the ligand that we discuss in Nature, is found exclusively at the apical, top part, of the cell. It's a growth factor."
The living, breathing rat is Vermeer's animal model of choice. "We took three different approaches," she recounted. "The first was that we excised their trachea and washed out the airway surface liquid. Then we sutured - sealed off - both ends of the tracheas. In other rats, we isolated the trachea - didn't do anything to wash away that lining off the top of the cells. Just left that alone and sutured both ends of the tracheas. Then we put them in a solution that would open up the tight junctions. Our idea was, in those tracheas where we washed away the signaling molecule, even if the tight junction were opened, even if that gate now swung wide, we didn't expect an effect, because we'd washed away the heregulin.
"In their tracheas, where we didn't wash anything away, if we opened up the gate, we should see a signal. In fact it was something present only at the top of the cell, and that's actually what we saw."
Scraping The Bottom Of The Trachea
"We have a third in vivo experiment now completed, also with rats," Vermeer continued, "in which another way that the tight junction can be weakened or eliminated is by mechanical injury. We took a little brush and put it down the trachea of rats and pulled it out once. So that essentially scraped the trachea lining and made an injury there. And we asked the same question: As a consequence of this mechanical injury, did we now see that the signaling molecule was able to access and activate the receptor? And that's exactly what we found.
"A fourth experiment we're following up on is whether heregulin, the signaling growth factor molecule, leads to an increase in one of these respiratory cell types. Right now it looks as if we may be getting an increase in the goblet cell population. Ciliated cells sweep away particulate matter that we've inhaled, and mucus is also very important for that. So one of their problems in asthma and cystic fibrosis is if you have too much mucus, produced by too many goblet cells. Heregulin, we think, is now activating the receptor, and in consequence would generate more goblet cells, which is exactly what we see in the human disease state. Too many goblet cells mean too much mucus, which would plug up a patient's airways."
The Nature paper's senior author, Michael Welsh, commented, "The results of this study might also be relevant to many other biological systems. We speculate that might mean that signaling molecules could gain access to their receptors, which might stimulate cell growth. When cancer cells grow," he concluded, "they often lose their tight-junction barrier function."