Heterogeneity of airway wall dimensions in humans: a critical determinant of lung function in asthmatics and non-asthmatics

Airway remodeling is a cardinal feature of diseases such as asthma. Previous measurements and modeling of the airways of non-asthmatics vs. asthmatics have shown that increased airway smooth muscle contributes substantially to remodeling and the resultant narrowing of the airway lumen. However, the assumption in models based on lung morphometry is that narrowing occurs proportionately, i.e. homogenously along the branches of the bronchial tree. In this elegant modeling paper based on measurements of airway lumens from asthmatics vs. non-asthmatics, Pascoe et al. demonstrate for the first time that there is profound heterogeneity in the extent of remodeling along the different branches of the bronchial tree, with small airways contributing particularly to such heterogeneity. The predicted physiological importance of this heterogeneity in airwaywall dimensions of non-asthmatics and asthmatics lies in their contribution to airway hyperresponsiveness (the model predicting a leftward shift in the likely dose response to bronchoconstrictor agonist). Here, closure of small airways is predicted, as is known to occur in obstructive airway disease. However, what is interesting is that a disproportionate or greater heterogeneity in asthmatic airways does not necessarily predict AHR, but it is the increase in airway wall dimensions that does. The appeal of such elegant modeling studies in human lungs of asthmatics vs. non-asthmatics lies in emphasizing the need for more mechanistic studies on remodeling, particularly of the small airways that contribute to premature closure and obstructive disease, and importantly in the need for improved imaging techniques of the small airways, particularly under standardized conditions that would allow for accurate and sensitive assessment of the extent of airway remodeling, its changes with time (e.g. in aging or asthma in the elderly) or responsiveness to therapies.

Y.S. Prakash
Deputy Editor

Link to the manuscript ; Pascone, CD et al...

Dysregulated Nox4 ubiquitination contributes to redox imbalance and age- 2 related severity of acute lung injury

Why do we age?  In a previous paper, Dr. Hecker demonstrated that imbalance among reactive species, contributed by NOX4 and antioxidant defenses, is a major factor in aging.  In this paper, Dr. Hecker demonstrated that aged mice develop more severe lung injury than younger mice when given LPS and then ventilated (a double hit model of injury).  This mimics what is observed in the clinic, i.e. older people are at a higher risk of ARDS than younger people after trauma.  Dr. Hecker followed up this in vivo observations with in studies on senescent microvascular cells and showed that they suffered significantly higher injury than young endothelial cells when exposed to LPS.  Furthermore, they demonstrated that NOX4 was upregulated in both old (senescent)  and young endothelial cells but in senescent endothelial cells NOX4 was not ubiquinated and thus continue to produce reactive species.  This findings increase our understanding of why we age.  Furthermore, they point out that we all should eat more antioxidants or take more vitamin C

Sadis Matalon

Click here for full paper  http://ajplung.physiology.org/content/early/2017/01/03/ajplung.00305.2016