Location and mechanisms of pulmonary vascular volume changes

We examined the influence of changing outflow pressure, P out, on the vascular and extravascular volumes (QV and QEV, respectively, as measured by indicator dilution) and on the outflow occlusion pressures in isolated dog lung lobes perfused with constant flow. Changing P out had a substantial effect on QV, but not on QEV, whether P out was less than or greater than alveolar pressure, PA. Since QEV did not change with QV, recruitment of previously unperfused vessels did not appear to contribute substantially to the increases in QV when P out was increased. The rapid jump in P out immediately following outflow occlusion was virtually independent of the difference between PA and P out suggesting that the alveolar vessels were an important volume storage site when P out was low relative to PA. We conclude that, over a certain range of pressures, alveolar vessel volume can be controlled by venous pressure even when the change in venous pressure has little effect on arterial pressure (zone 2). Further, we conclude that in zone 3 and within the transition from zone 2 to zone 3 increases in the intralobar blood volume occurring within the alveolar vessels may not require recruitment in the sense of opening of previously unperfused vessels.     

Distensibility of small arteries of the dog lung.

To obtain in situ measurements of the distensibility of small (100- to 1,000-microns-diam) pulmonary arterial vessels of the dog lung, X-ray angiograms were obtained from isolated lung lobes with the vascular pressure adjusted to various levels. The in situ diameter-pressure relationships were compared with the diameter-pressure relationships for small arteries that were dissected free from the lungs and cannulated with small glass pipettes for the measurement of diameter and transmural pressure. The diameter-vascular or diameter-transmural pressure curves from both in situ and cannulated vessels were sufficiently linear in the pressure range studied (0-30 Torr) that they could be characterized by linear regression to obtain estimates of D0, the diameter at zero vascular pressure, and beta, the change in diameter (micron) per Torr change in pressure. The vessel distensibility coefficient (alpha) was defined as alpha = beta/D0. The mean values of alpha were approximately 2.0 +/- 0.8%/Torr (SD) for the in situ vessels and 1.7 +/- 0.6%/Torr for the cannulated vessels, with no statistically significant difference between the two methods. The influence of vasoconstriction elicited by serotonin was evaluated in the in situ vessels. Serotonin-induced vasoconstriction caused a decrease in D0 and little change in alpha.     

Effect of vasoconstriction on longitudinal distribution of pulmonary vascular pressure and volume

We used an improved version of the low-viscosity bolus method to evaluate longitudinal (arterial-to-venous) differences in the sensitivity of the dog lung lobe vasculature to selected vasoconstrictor stimuli, including hypoxia, and serotonin, histamine, and norepinephrine infusions. This method revealed a bimodal distribution of local vascular resistance vs. cumulative vascular volume under the zone 3 conditions studied. Our interpretation of the two modes of relatively high resistance is that they correspond to high resistance per unit volume segments of the arteries and veins upstream and downstream from the relatively low resistance per unit volume capillary bed. Thus an increase in the height of the upstream and downstream modes of the resistance distribution suggests constriction in small arteries and veins, respectively. Horizontal displacement of the modes along the cumulative volume axis suggests changes in the distribution of volume among the arteries, veins, and capillary bed. By use of these criteria, the results are consistent with the concept that each of the vasoconstrictor stimuli studied had a different longitudinal response pattern. Hypoxia constricted mainly small arteries, whereas serotonin constricted small and large arteries. Histamine constricted large and small veins, and norepinephrine constricted large and small veins and arteries.     

Flow-induced vasodilation in the ferret lung

Chammas, Joseph H., David. A. Rickaby, Margarita Guarin,John H. Linehan, Christopher C. Hanger, and Christopher A. Dawson. Flow-induced vasodilation in the ferret lung. J. Appl. Physiol. 83(2): 495-502, 1997.To examinethe possibility that shear stress may be a pulmonary vasodilatorstimulus, we studied the effect of changing blood flow on the diametersof small pulmonary arteries in isolated perfused ferret lung lobes. Thearteries studied were in the ~0.3- to 1.3-mm-diameter range, and thediameters were measured by using microfocal X-ray imaging. Thediameters were measured at two flow rates, 10 and 40 ml/min, with theintravascular pressure in the measured vessels the same at the two flowrates as the result of venous pressure adjustment. The response to a change in flow was studied under both normoxic and hypoxic conditions. Hypoxia was used to elevate pulmonary arterial tone to increase thelikelihood of detecting a vasodilator response. Under normoxic conditions, changing flow had little effect on the arterial diameters, but under hypoxic conditions the arteries were consistently larger atthe higher flow than at the lower flow, even though the distending pressure was the same at the two flow rates. The results are consistent with the hypothesis that shear stress is a pulmonary vasodilator stimulus.

     

Distributions of vascular pressure and resistance in the lung

The low-viscosity bolus method was used to determine the longitudinal distributions of vascular resistance and intravascular pressure with respect to cumulative vascular volume from the lobar artery to the lobar vein in isolated dog lung lobes near functional residual capacity under zone 3 conditions. We found that the resistance distribution had two modes, a larger one upstream and a smaller one downstream from a local minimum. Over the range of vascular pressures studied the total vascular resistance decreased and the vascular volume increased with increasing vascular pressure. However, the shape of the normalized resistance distribution was independent of vascular pressure. Comparisons of the resistance distributions with the distributions of arterial, capillary, and venous volumes suggest that the modes represent regions of relatively high resistance proximal and distal to the capillary bed. These results are consistent with the concept that within the lobar vascular bed the highest resistance per unit blood volume is in the smallest arteries and veins, as suggested by morphometric data from other sources.     

Interaction of the coccolithophore Gephyrocapsa oceanica with its carbon environment: response to a recreated high-CO2 geological past

Coccolithophores have played a key role in the carbon cycle since becoming dominant in the Cretaceous ocean, and their influence depends fundamentally on how they interact with their external carbon environment. Because the photosynthetic carbon-fixing enzyme Rubisco requires high levels of CO(2) for effective catalysis, coccolithophores are known to induce carbon concentrating mechanisms (CCMs) to raise the level of dissolved inorganic carbon (DIC) in an 'internal pool'. The ocean carbon system has varied greatly over the geological past, suggesting that coccolithophore interactions with that external carbon environment will have changed in parallel. The widespread present-day coccolithophore Gephyrocapsa oceanica was acclimated here to a geological scale change in the seawater carbon system (five times higher DIC and alkalinity). Significant acclimation in response to the external carbon environment was demonstrated by a fourfold increase in the K(m) substrate concentration requirement for half-maximum photosynthetic carbon fixation rates (suggesting that CCMs were down-regulated when ambient carbon was more available). There was, however, no difference in growth rate, morphology or calcification, suggesting that calcification is not coupled to photosynthesis as one of the CCMs induced here and that productivity (growth rate and calcification) is not carbon-limited under representative present-day conditions. Beyond the kinetic parameters of photosynthesis, the only other indication of changed cell physiology seen was the increased fractionation of carbon isotopes into organic matter. These findings demonstrate that G. oceanica changes its carbon-use physiology to maintain consistent photosynthetic carbon fixation in concert with different levels of ambient DIC without changing its morphology or calcification.     

Rare copy number variations in adults with tetralogy of fallot implicate novel risk gene pathways

Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p?=?0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.     

Effect of atelectasis and surface tension on pulmonary vascular compliance

The effects of atelectasis and surface tension on the vascular volume and compliance in an isolated perfused dog lung lobe were studied using vascular occlusion and indicator-dilution methods. Measurements were made during atelectasis and again after the lobes were inflated with either a gas mixture (air) or 0.9% saline. Inflation with air resulted in a 20% increase in vascular volume (P less than 0.02), whereas saline inflation had no effect on vascular volume. Inflation with either air or saline increased static vascular compliance by approximately 58% (P less than 0.001) and dynamic vascular compliance by approximately 85% (P less than 0.001). The larger dynamic compliance in the inflated lobes appears to have been mainly due to a larger microvascular compliance. The results suggest that atelectasis can result in a stiffer pulmonary capillary bed. This effect appears to be due primarily to the reconfiguration of the lung tissue structure, because replacing the air with an incompressible fluid did not have the same effect.