On Becoming a Domestic and Laboratory Goddess

Happy New Year, dear Isis! FYI, your RSS feed is not working for me in Bloglines any longer. Not sure what's up wit dat.

Posted by: Candid Engineer | January 1, 2009 7:56 PM

I have only seen the title of the editorial and the abstract of the article but I am quite familiar with exhaled NO and its use as a marker for asthma. There is considerable dogma in the NO research field, much of which is wrong. The idea that too much NO is causal, or is bad for asthma is one of those dogmas that is wrong.

Exhaled NO may be an ok marker for asthma, but exhaled NO is an effect, not a cause. Exhaled NO is tricky to measure. The nasal passages produce NO (normally a couple hundred ppb in inhaled air) and when flow is occluded, the steady state NO concentration is about 20 ppm (yes, ppm). Exhaled NO levels are variable, and depend on a lot of different things. In "normal" individuals it is ~10 ppb, in people with asthma it might be 15 ppb. Different, and statistically significant, but is it clinically significant? These levels are about 3 orders of magnitude less than what can naturally be produced in the nasal passages. Commensal bacteria on the tongue produce NO, especially after consumption of a high nitrate meal (i.e. lettuce which has a couple thousand ppm nitrate). The head space in the stomach can have high NO levels (due to nitrite in saliva reduce to NO at low pH) levels up to 80 ppm have been measured. Measuring NO levels in exhaled air is tricky because there are a lot of artifacts that can make the measurements wrong.

Inhaling cold and/or dry air reduces the NO production in the nasal passages. I very strongly suspect that this is the mechanism behind the acute increase in heart disease fatalities with an acute drop in temperature (very easy to see in large data sets correlating heart disease fatalities with weather).

Asthma occurs when mast cells become hyper-reactive. Those hyper-reactive mast cells degranulate and release histamine and proteases which activate other mast cells and cause local inflammation. The problem in asthma is not enough NO in the first place, because low NO is one of the things that makes mast cells hyper-reactive. Asthma is fundamentally a dysregulation of the sensitivity of mast cells. That dysregulation occurs because the basal NO level is too low.

When mast cells degranulate, they make superoxide which destroys NO making adjacent mast cells more reactive. My working hypothesis is that mast cells function that way to get a very robust "turn on" of immune function when activated even by a small signal. If even a few nasties trigger a mast cell, your immune system wants to wipe them out before they can get a pseudopod-hold. The way to do that is with the Powell Doctrine of overwhelming force. If you have a high enough basal NO level, the range of the ROS mediated mast cell depletion of NO is limited. If you don't have enough basal NO, the low NO can propagate farther, and can even become systemic (as in asthma or atopy).

Their conclusion is completely correct, chasing after exhaled NO is barking up the wrong tree. I would go farther and say it won't tell us anything about normal lung function (and would have said that even before seeing this paper (which I still haven't seen). The increased NO observed is an effect, not a cause. The way to decrease asthma is by increasing NO levels, but inhalation isn't a great way to do it therapeutically because it can only be done in a hospital setting.

I haven't had breakfast yet, after I do, I will write a more detailed response.

Posted by: daedalus2u | January 2, 2009 9:24 AM