LAUSR

Hypoxic pulmonary vasoconstriction (HPV) is believed to play an important homeostatic role in asthma and other heterogeneous lung diseases by redistributing blood flow from regions that are relatively poorly ventilated, and thus hypoxic, to those with normal ventilation that are normoxic. Such redistribution mitigates the arterial hypoxemia arising from blood flow to regions with low V : /Q : ratios. In this issue of the Journal, Kelly and colleagues (pp. 834–844) explore HPV in subjects with asthma by using a sophisticated protocol that examines both the effects of induced bronchoconstriction and the influence of the regional hypoxia that is believed to be the stimulus for regional HPV (1). They measured ventilation and perfusion of small lung regions using positron emission tomography–computed tomography before and after methacholine challenge. To measure local perfusion, they injected a bolus of Nitrogen-13 (NN) into the blood and observed the rate of NN elaboration into the lung during a 30-second breath-hold. Then, during the subsequent normal breathing, they measured regional ventilation by observing the rate of NN washout. To test the local effects of bronchoconstriction, the authors performed these measurements before and after methacholine challenge, and to test the effects of the regional hypoxia that gives rise to HPV, they performed the series of experiments described above while the subjects breathed room air and 80% oxygen. They computed regional PO2 values from the V : /Q : data using standard blood chemistry equations, with the usual assumptions concerning cardiac output and other variables. Not surprisingly, they found that methacholine challenge caused a heterogeneous redistribution of ventilation from some regions of the lung to others. During room-air breathing, the leastventilated regions became substantially hypoxic, and there was a substantial redistribution of perfusion away from the hypoxic regions to regions with better ventilation, consistent with HPV. Moreover, during 80% oxygen breathing, there was substantially less regional hypoxia and substantially less redistribution of perfusion from regions of low ventilation to better-ventilated regions, as would be expected if reduced local hypoxia caused a decrease in HPV. However, a subgroup analysis of the regions with the greatest reduction in V : /Q : ratios revealed that many poorly ventilated regions that were normoxic or even hyperoxic nonetheless exhibited reduced perfusion after bronchoconstriction. How could bronchoconstriction have caused blood redistribution from the most obstructed regions in the absence of local hypoxia or HPV? The authors considered several mechanisms that could account for such redistribution. Direct activation of vascular smooth muscle by methacholine was considered, but it was believed to be unlikely in light of numerous studies showing negligible effects of methacholine and other cholinergic agents on pulmonary vascular smooth muscle. Bronchoconstriction might have caused local dynamic hyperinflation to distend the alveoli and thus reduce perfusion in the most hyperinflated regions. However, analysis of the high-resolution computed tomography data showed that bronchoconstriction induced only small increases in regional air volumes, on the order of 1–2%, which the authors believed were not sufficient to account for the observed reductions in regional perfusion by z10%. By eliminating other mechanisms, they concluded that a mechanical interaction between airways and vessels was the most likely explanation for their findings. Of course, the lungs comprise two intimately connected branching networks (for air and blood) running in parallel and embedded within the parenchyma, a situation that invites important mechanical interactions among these elements. It is known that at any given lung volume, pulmonary elastic recoil pressure increases during bronchoconstriction, e.g., with vagal stimulation or the administration of bronchoconstrictive drugs (2–4). These effects are believed to be largely due to constriction of the most peripheral airways and/or alveolar ducts (5, 6). The mechanism of this interaction is relatively easy to envision, as during bronchoconstriction the airways get smaller and apply increased tension on their connections to the surrounding parenchyma, increasing tension in tissue elements and thus increasing the pulmonary elastic recoil pressure (6). The effects of bronchoconstriction on the redistribution of perfusion are more difficult to explain. It is tempting to invoke communication via the common peribronchial pressure that surrounds the distal airways and pulmonary arteries in the peribronchial space (7). Under normal conditions, the peribronchial pressure is close to the pleural pressure, but as the airways narrow with bronchoconstriction, pressure in the peribronchial space decreases. This decreased peribronchial pressure should, if anything, increase the transmural distending pressure in the pulmonary vessels, keeping them open. However, Kelly and colleagues show that regions with greater airway constriction, that is, those with greater hypoxia, exhibit the opposite effect: a regional decrease in perfusion (8). The authors propose that distortion or “direct translocation” of the pulmonary vasculature by bronchoconstriction could mediate the required increase in regional vascular impedance. The details of such compressive mechanisms remain to be explored. Notwithstanding the necessarily speculative nature of their final conclusions, the authors are to be commended for this study, which addresses an important fundamental feature of pulmonary physiology and presents a new mechanism that could redistribute perfusion from bronchoconstricted regions. The present study builds on many years of human and animal experimentation by this group of authors using sophisticated techniques to image physiological phenomena. We can be optimistic that further insights will be coming from research of this type. n Originally Published in Press as DOI: 10.1164/rccm.201706-1260ED on July 21, 2017