Effect of alveolar hypoxia on regional pulmonary perfusion

We examined the effects of varying levels of alveolar hypoxia on regional distribution of pulmonary blood flow (QL) in control-ventilated sheep. Regional distribution of QL was measured using 15-micron-diam labeled microspheres during the base-line period and at two levels of hypoxemia (arterial O2 partial pressure 44 and 20 Torr). During the base-line period, regional distribution of QL in the prone position was uniform [14 +/- 4% (SE) of QL/g bloodless dry lung wt in the upper lung and 16 +/- 2% of QL/g in the dependent lung]. During hypoxemia, however, the regional distribution of QL increased in the upper lung (20 +/- 3% of QL/g) while it decreased in the dependent lung (10 +/- 2% of QL/g). The degree of flow distribution was proportional to the severity of hypoxemia. The flow distribution was not associated with significant increases in pulmonary blood flow (2.0 +/- 0.4----2.4 +/- 0.5----2.6 +/- 0.1 l/min) but was associated with increases in mean pulmonary arterial pressure (17.8 +/- 1.3----21.7 +/- 1.1----29.0 +/- 3.8 Torr). Therefore alveolar hypoxia results in a relative increase in regional pulmonary perfusion to the upper lung, which depends on the level of pulmonary hypertension. The increased upper lung perfusion may be due to recruitment in the upper lung or to vasodilation in this region.     

Interaction between cold and altitude exposure on pulmonary circulation of cattle

Hereford calves were exposed in a temperature-controlled hypobaric chamber to environmental temperatures of -2 to 1 degree C (cold) at altitudes of 1,524 m (resident altitude) and 3,048 m 1) to characterize the effects of cold exposure on the pulmonary circulation; 2) to examine the role of cold-induced hypoventilation on the pulmonary circulation; and 3) to examine the interaction between cold and hypoxia on the pulmonary circulation. Cold exposure produced a significant increase in pulmonary arterial pressure (Ppa), pulmonary arterial wedge pressure (Ppaw), and pulmonary vascular resistance (PVR) at both 1,524 and 3,048 m without affecting cardiac output. Concomitantly, cold exposure caused reductions in minute ventilation, respiratory rate, end-tidal O2 tension (PETO2), and arterial O2 tension (PaO2). Tidal volume, end-tidal CO2 tension, and arterial CO2 tension increased. Neither arterial pH nor O2 consumption changed during cold exposure. These results indicated that both pulmonary arterial and venous vasoconstriction were responsible for the pulmonary hypertension associated with cold exposure. Acute exposure to 3,048 m during cold exposure produced increases in Ppa and PVR that were similar to those elicited by cold exposure at 1,524. It was concluded that altitude exposure neither attenuated nor potentiated the effect of cold exposure on the pulmonary circulation; rather, altitude and cold exposure interacted additively. O2 administered during cold exposure to restore PETO2 and PaO2 to control values partially restored Ppa and PVR to control values. This suggested that a portion of the pulmonary hypertension associated with cold exposure was due to hypoxic pulmonary vasoconstriction elicited by the cold-induced alveolar hypoventilation.     

Three-dimensional reconstruction of alveoli in the rat lung for pressure-volume relationships

To determine alveolar pressure-volume relationships, alveolar three-dimensional reconstructions were prepared from lungs fixed by vascular perfusion at various points on the pressure-volume curve. Lungs from male Sprague-Dawley rats were fixed by perfusion through the pulmonary artery following a pressure-volume maneuver to the desired pressure point on either the inflation or deflation curve. Tissue samples from lungs were serially sectioned for determination of the volume fraction of alveoli and alveolar ducts and reconstruction of alveoli. Alveoli from lungs fixed at 5 cmH2O on the deflation curve (approximating functional residual volume) had a volume of 173 X 10(3) microns3, a surface area of 11,529 microns2, a mouth opening diameter of 72.7 microns, and a mean caliper diameter of 91.8 micron (SE). Alveolar shape changes during deflation from total lung capacity to residual volume was first (30 to 10 cmH2O) associated with little change in the diameter of the alveoli (102.7 +/- 2.4 to 100.3 +/- 3.3 microns). In the range overlapping normal breathing (10 to 0 cmH2O) there was a substantial decrease in diameter (100.3 +/- 3.3 to 43.3 +/- 2.3 microns). These measurements and others made on the relative changes in the dimensions of the alveolus suggest that the elastic network, particularly around the alveolar ducts, are predominant in determining lung behavior near the volume expansion limits of the lung while the elastic and surface tension properties of the alveoli are predominant in the volume range around functional residual capacity.     

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured "on-line" using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.     

Zone 2 and zone 3 pulmonary blood flow

In the West model of zonal distribution of pulmonary blood flow, increases in flow down zone 2 are attributed to an increase in driving pressure and a decrease in resistance resulting from recruitment and distension. The increase in flow down zone 3 is attributed to a decrease in resistance only. Recent studies indicate that, besides the pressure required to maintain flow through a vessel, there is an added pressure cost that must be overcome in order to initiate flow. These additional pressure costs are designated critical pressures (Pcrit). Because Pcrit exceed alveolar pressure, the distinction between zones in the West model becomes less secure, and the explanation for the increase in flow even in West zone 3 requires reexamination. We used two methods to test the hypothesis that the Pcrit is the pertinent backpressure to flow even in zone 3, when the pulmonary venous pressure (Ppv) exceeds alveolar pressure (PA) but is less than Pcrit in the isolated canine left caudal lobe. First, PA was maintained at 5 cmH2O, and pressure flow (P-Q) characteristics were obtained in zone 2 and zone 3. Next, with PA still at 5 cmH2O, we maintained a constant flow and measured the change in pulmonary arterial pressure as Ppv was varied. Both techniques indicated that the pertinent backpressure to flow was the greater of either Pcrit or Ppv and that PA was never the pertinent backpressure to flow. Also, our results indicate no significant change in the geometry of the flow channels between zone 2 and zone 3. These findings refine the zonal model of the pulmonary circulation.     

Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling.

The present study utilized a novel transgenic mouse model that expresses an inducible dominant negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGFbetaRII mouse) to test the hypothesis that TGF-beta signaling plays an important role in the pathogenesis of chronic hypoxia-induced increases in pulmonary arterial pressure and vascular and alveolar remodeling. Nine- to 10-wk-old male DnTGFbetaRII and control nontransgenic (NTG) mice were exposed to normobaric hypoxia (10% O2) or air for 6 wk. Expression of DnTGFbetaRII was induced by drinking 25 mM ZnSO4 water beginning 1 wk before hypoxic exposure. Hypoxia-induced increases in right ventricular pressure, right ventricular mass, pulmonary arterial remodeling, and muscularization were greatly attenuated in DnTGFbetaRII mice compared with NTG controls. Furthermore, the stimulatory effects of hypoxic exposure on pulmonary arterial and alveolar collagen content, appearance of alpha-smooth muscle actin-positive cells in alveolar parenchyma, and expression of extracellular matrix molecule (including collagen I and III, periostin, and osteopontin) mRNA in whole lung were abrogated in DnTGFbetaRII mice compared with NTG controls. Hypoxic exposure had no effect on systemic arterial pressure or heart rate in either strain. These data support the hypothesis that endogenous TGF-beta plays an important role in pulmonary vascular adaptation to chronic hypoxia and that disruption of TGF-beta signaling attenuates hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial hypertrophy and muscularization, alveolar remodeling, and expression of extracellular matrix mRNA in whole lung.     

Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days

Morphological, biochemical, and physiological studies were done on rats exposed to 60% O2 for 7 days. This exposure did not induce O2 tolerance but instead caused a significant decrease in survival time of animals subsequently exposed to pure O2. The activity of lung superoxide dismutases and glucose-6-phosphate dehydrogenase were unchanged after exposure to 60% O2. A decrease in lung compliance was suggested by changes in the total lung capacity and in the pressure-volume curves of excised lungs. Ventilation of these animals with large tidal excursion resulted in pulmonary edema. Morphometric analyses revealed a significant decrease in alveolar air volume and an increase in the number of alveolar macrophages. The most significant lesions involved the pulmonary vascular bed. The volume and thickness of the capillary endothelium was decreased. There were focal areas of pericapillary fluid accumulations, and a number of the smaller vessels had perivascular edema. These findings suggest that significant pulmonary injury occurs in rats exposed to 60% O2 and that the primary site of injury is the pulmonary capillary endothelium.     

Effects of Triiodothyronine (T3) Supplementation Upon Ozone-Induced Lung Injury

Ozone exposure results in an acute decrease in the serum levels of thyroid hormones; the physiologic sequelae of this are unclear. Whereas thyroid hormone supplementation appears to benefit pulmonary function in septic, oxyradical models of injury, thyroid hormone increases ozone toxicity. We demonstrated an increase in metabolic rate and pulmonary injury in lungs from ozone exposed, T₃ treated animals. This was evidenced by an increase in pulmonary weight gain, vascular perfusion pressure, and decrease in compliance in the supplemented animals. However, an increase in alkane generation, as an index of lipid peroxidation, was not seen in the ozone exposed, hormonally treated animals. This suggests that although thyroid hormone supplementation increases metabolic rate and ozone toxicity, an increased rate of lipid peroxidation plays a minimal role.     

Effect of increased alveolar surface tension on segmental pulmonary vascular resistance

The site of change in pulmonary vascular resistance (PVR) after surfactant displacement with the detergent diocytl sodium sulfosuccinate (OT) was studied in the isolated canine left lower lobe preparation. Changes in PVR were assessed using the arterial and venous occlusion technique and the vascular pressure-flow relationship. Changes in alveolar surface tension were confirmed from measurements of pulmonary compliance as well as from measurements of surface tension of extracts from lung homogenates. After surfactant depletion (the perfusion rate constant) the total pressure gradient (delta PT) across the lobe increased from 13.4 +/- 1 to 17.1 +/- 0.8 mmHg. This increase in delta PT was associated with a significant increase in the arterial and venous gradients (3.7 +/- 0.3 to 4.9 +/- 0.4 and 5.7 +/- 0.5 to 9.4 +/- 0.6 mmHg, respectively) and a decrease in middle pressure gradient (4.1 +/- 0.8 to 2.9 +/- 0.6 mmHg). The vascular pressure-flow relationship supported these findings and showed that the mean slope increased by 52% (P less than 0.05), whereas the pressure intercept decreased slightly but not significantly (3.7 +/- 0.7 to 3.2 +/- 0.8 mmHg). These results suggest that the resistance of arteries and veins increases, whereas the resistance of the middle segment decreases after surfactant depletion. These effects were apparently due to surface tension that acts directly on the capillary wall. Direct visualization of subpleural capillaries supported the notion that capillaries become distended and recruited as alveolar surface tension increases. In the normal lung (perfused at constant-flow rate) changes in alveolar pressure (Palv) were transmitted fully to the capillaries as suggested by equal changes in pulmonary arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of microvascular circulation on peripheral lung stability

The involvement of pulmonary circulation in the mechanical properties was studied in isolated rat lungs. Pulmonary input impedance (ZL) was measured at a mean transpulmonary pressure (Ptpmean) of 2 cmH2O before and after physiological perfusion with either blood or albumin. In these lungs and in a group of unperfused lungs, ZL was also measured at Ptpmean values between 1 and 8 cmH2O. Airway resistance (Raw) and parenchymal damping (G) and elastance (H) were estimated from ZL. End-expiratory lung volume (EELV) was measured by immersion before and after blood perfusion. The orientation of the elastin fibers relative to the basal membrane was assessed in additional unperfused and blood-perfused lungs. Pressurization of the pulmonary capillaries significantly decreased H by 31.5 +/- 3.7% and 18.7 +/- 2.7% for blood and albumin, respectively. Perfusion had no effect on Raw but markedly altered the Ptpmean dependences of G and H < 4 cmH2O, with significantly lower values than in the unperfused lungs. At a Ptpmean of 2 cmH2O, EELV increased by 31 +/- 11% (P = 0.01) following pressurization of the capillaries, and the elastin fibers became more parallel to the basal membrane. Because the organization of elastin fibers results in smaller H values of the individual alveolus, the higher H in the unperfused lungs is probably due to a partial alveolar collapse leading to a loss in lung volume. We conclude that the physiological pressure in the pulmonary capillaries is an important mechanical factor in the maintenance of the stability of the alveolar architecture.     

Downregulation of hypoxic vasoconstriction by chronic hypoxia in rabbits: effects of nitric oxide

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange. Chronic alveolar hypoxia results in vascular remodeling and pulmonary hypertension. Previous studies have reported conflicting results of the effect of chronic alveolar hypoxia on pulmonary vasoreactivity and the contribution of nitric oxide (NO), which may be related to species and strain differences as well as to the duration of chronic hypoxia. Therefore, we investigated the impact of chronic hypoxia on HPV in rabbits, with a focus on lung NO synthesis. After exposure of the animals to normobaric hypoxia (10% O(2)) for 1 day to 10 wk, vascular reactivity was investigated in ex vivo perfused normoxic ventilated lungs. Chronic hypoxia induced right heart hypertrophy and increased normoxic vascular tone within weeks. The vasoconstrictor response to an acute hypoxic challenge was strongly downregulated within 5 days, whereas the vasoconstrictor response to the thromboxane mimetic U-46619 was maintained. The rapid downregulation of HPV was apparently not linked to changes in the lung vascular NO system, detectable in the exhaled gas and by pharmacological blockage of NO synthesis. Treatment of the animals with long-term inhaled NO reduced right heart hypertrophy and partially maintained the reactivity to acute hypoxia, without any impact on the endogenous NO system being noted. We conclude that chronic hypoxia causes rapid downregulation of acute HPV as a specific event, preceding the development of major pulmonary hypertension and being independent of the lung vascular NO system. Long-term NO inhalation partially maintains the strength of the hypoxic vasoconstrictor response.     

Alveolar pressure in fluid-filled occluded lung segments during permeability edema

In a model of increased hydrostatic pressure pulmonary edema Parker et al. (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44: 267-276, 1978) demonstrated that alveolar pressure in occluded fluid-filled lung segments was determined primarily by interstitial fluid pressure. Alveolar pressure was subatmospheric at base line and rose with time as hydrostatic pressure was increased and pulmonary edema developed. To further test the hypothesis that fluid-filled alveolar pressure is determined by interstitial pressure we produced permeability pulmonary edema-constant hydrostatic pressure. After intravenous injection of oleic acid in dogs (0.01 mg/kg) the alveolar pressure rose from -6.85 +/- 0.8 to +4.60 +/- 2.28 Torr (P less than 0.001) after 1 h and +6.68 +/- 2.67 Torr (P less than 0.01) after 3 h. This rise in alveolar fluid pressure coincided with the onset of pulmonary edema. Our experiments demonstrate that during permeability pulmonary edema with constant capillary hydrostatic pressures, as with hemodynamic edema, alveolar pressure of fluid-filled segments seems to be determined by interstitial pressures.     

Comparison of pulmonary vascular function and structure in early and established hypoxic pulmonary hypertension in rats

In pulmonary hypertension, changes in pulmonary vascular structure and function contribute to the elevation in pulmonary artery pressure. The time-courses for changes in function, unlike structure, are not well characterised. Medial hypertrophy and neomuscularisation and reactivity to vasoactive agents were examined in parallel in main and intralobar pulmonary arteries and salt-perfused lungs from rats exposed to hypoxia (10% O2) for 1 and 4 weeks (early and established pulmonary hypertension, respectively). After 1 week of hypoxia, in isolated main and intralobar arteries, contractions to 5-hydroxytryptamine and U46619 (thromboxane-mimetic) were increased whereas contractions to angiotensins I and II and relaxations to acetylcholine were reduced. These alterations varied quantitatively between main and intralobar arteries and, in many instances, regressed between 1 and 4 weeks. The alterations in reactivity did not necessarily link chronologically with alterations in structure. In perfused lungs, constrictor responses to acute alveolar hypoxia were unchanged after 1 week but were increased after 4 weeks, in conjunction with the neomuscularisation of distal alveolar arteries. The data suggest that in hypoxic pulmonary hypertension, the contribution of altered pulmonary vascular reactivity to the increase in pulmonary artery pressure may be particularly important in the early stages of the disease.     

Capillary perfusion patterns in single alveolar walls.

We studied capillary perfusion patterns in single alveolar walls through a transparent thoracic window implanted in pentobarbital-anesthetized dogs. The capillaries were maximally opened by brief inflation of a balloon in the left atrium to raise pressure. After the balloon was deflated and pulmonary hemodynamics returned to zone 2 baseline conditions, the capillaries that remained perfused in the observed field were videotaped with the use of in vivo microscopy. The cycle of elevated pressure and baseline observation was repeated three times. Perfusion of different capillaries during each of the observations would imply that the capillaries had characteristics that permitted flow to switch between segments. Perfusion of a specific set of pathways through the network each time would demonstrate that flowing blood sought a unique and repeatable combination of segments, presumably with the least total pathway resistance. We found that the same capillary segments were perfused 79% of the time, a strong indication that a reproducible combination of individual segmental resistances determined the predominant pattern of pulmonary capillary perfusion.     

Interstitial fibrosis and collateral ventilation

Interstitial fibrosis may increase resistance to collateral flow (Rcoll) because of decreased lung volume and destruction of collateral channels or it may decrease Rcoll because of emphysematous changes around fibrotic regions. In addition, if interstitial fibrosis involves a small region of lung periphery, interdependence from surrounding unaffected lung should produce relatively large changes in volume of the fibrotic region during lung inflation. We studied the effects of interstitial fibrosis on collateral airflow by measuring Rcoll at functional residual capacity (FRC) in nine mongrel dogs before and 28 days after the local instillation of bleomycin into selected lung segments. In six of these dogs Rcoll was also measured at a higher lung volume (transpulmonary pressure = 12 cmH2O above FRC pressure). Rcoll increased in fibrotic lung segments following local treatment with bleomycin. With lung inflation (high transpulmonary pressure) Rcoll fell a similar proportion in fibrotic and nonfibrotic lung regions. These observations suggest that collateral resistance increases in fibrotic segments because lung volume decreases or because collateral pathways are involved directly in the fibrotic process. Compensatory increases in collateral communications do not occur. In addition, pulmonary interdependence does not cause disproportionate increases in volume and decreases in Rcoll of the fibrotic region during lung inflation.     

Hypoxia and angiotensin II infusion redistribute lung blood flow in lambs

To assess the effects of alveolar hypoxia and angiotensin II infusion on distribution of blood flow to the lung we performed perfusion lung scans on anesthetized mechanically ventilated lambs. Scans were obtained by injecting 1-2 mCi of technetium-labeled albumin macroaggregates as the lambs were ventilated with air, with 10-14% O2 in N2, or with air while receiving angiotensin II intravenously. We found that both alveolar hypoxia and infusion of angiotensin II increased pulmonary vascular resistance and redistributed blood flow from the mid and lower lung regions towards the upper posterior region of the lung. We assessed the effects of angiotensin II infusion on filtration pressure in six lambs by measuring the rate of lung lymph flow and the protein concentration of samples of lung lymph. We found that angiotensin II infusion increased pulmonary arterial pressure 50%, lung lymph flow 90%, and decreased the concentration of protein in lymph relative to plasma. These results are identical to those seen when filtration pressure increases during alveolar hypoxia. We conclude that alveolar hypoxia and angiotensin II infusion both increase fluid filtration in the lung by increasing filtration pressure. The increase in filtration pressure may be the result of a redistribution of blood flow in the lung with relative overperfusion of vessels in some areas and transmission of the elevated pulmonary arterial pressure to fluid-exchanging sites in those vessels.     

Pulmonary edema: ischemia reperfusion endothelial injury and its reversal by c-AMP.

A review of the factors that oppose pulmonary edema formation (alveolar flooding) when capillary pressure is elevated are presented for a normal capillary endothelial barrier and for damaged endothelium associated with ischemia/reperfusion in rabbit, rat, and dog lungs. Normally, tissue pressure, the plasma protein osmotic pressure gradient acting across the capillary wall and lymph flow (Edema Safety Factors) increase to prevent the build-up of fluid in the lung's interstitium when capillary pressure increases. No measureable alveolar edema fluid accumulates until capillary pressure exceeds 30 mmHg. When the capillary wall has been damaged, interstitial edema develops at lower capillary pressures because the plasma protein osmotic pressure will not change greatly to oppose capillary filtration, but lymph flow increases to very high levels to remove the increased filtrate and the result is that capillary pressures can increase to 20-25 mmHg before alveolar flooding results. In addition, the mechanisms responsible for producing pulmonary endothelial damage with ischemia/reperfusion are reviewed and the effects of O2 radical scavengers, neutrophil depletion or altering their adherence to the endothelium, and increasing cAMP on reversing the damage to the pulmonary endothelium is presented.     

Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P < 0.001). Because the rate of alveolar fluid clearance in rats is closer to human rates, we studied beta-agonist therapy in rats, with hydrostatic pulmonary edema induced by volume overload (40% body wt infusion of Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.     

Modulatory effects of ozone on THP-1 cells in response to SP-A stimulation

Ozone (O(3)), a major component of air pollution and a strong oxidizing agent, can lead to lung injury associated with edema, inflammation, and epithelial cell damage. The effects of O(3) on pulmonary immune cells have been studied in various in vivo and in vitro systems. We have shown previously that O(3) exposure of surfactant protein (SP)-A decreases its ability to modulate proinflammatory cytokine production by cells of monocyte/macrophage lineage (THP-1 cells). In this report, we exposed THP-1 cells and/or native SP-A obtained from bronchoalveolar lavage of patients with alveolar proteinosis to O(3) and studied cytokine production and NF-kappaB signaling. The results showed 1) exposure of THP-1 cells to O(3) significantly decreased their ability to express TNF-alpha in response to SP-A; TNF-alpha production, under these conditions, was still significantly higher than basal (unstimulated) levels in filtered air-exposed THP-1 cells; 2) exposure of both THP-1 cells and SP-A to O(3) did not result in any significant differences in TNF-alpha expression compared with basal levels; 3) O(3) exposure of SP-A resulted in a decreased ability of SP-A to activate the NF-kappaB pathway, as assessed by the lack of significant increase and decrease of the nuclear p65 subunit of NF-kappaB and cytoplasmic IkappaBalpha, respectively; and 4) O(3) exposure of THP-1 cells resulted in a decrease in SP-A-mediated THP-1 cell responsiveness, which did not seem to be mediated via the classic NF-kappaB pathway. These findings indicate that O(3) exposure may mediate its effect on macrophage function both directly and indirectly (via SP-A oxidation) and by involving different mechanisms.     

Longitudinal distribution of vascular compliance in the canine lung

With an isolated perfused canine lung, the compliance of pulmonary circulation was measured and partitioned into components corresponding to alveolar and extra-alveolar compartments. When the lungs were in zone 3, changes in outflow pressure (delta Po) affected all portions of the vasculature causing a change in lung blood volume (delta V). Thus the ratio delta V/delta Po in zone 3 represented the compliance of the entire pulmonary circulation (Cp) plus that of the left atrium (Cla). When the lungs were in zone 2, changes in Po affected only the extra-alveolar vessels that were downstream from the site of critical closure in the alveolar vessels. Thus the ratio delta V/delta Po with forward flow in zone 2 represented the compliance of the venous extra-alveolar vessels (Cv) plus Cla. With reverse flow in zone 2, delta V/delta Po represented the compliance of the arterial extra-alveolar vessels (Ca). The compliance of the alveolar compartment (Calv) was calculated from the difference between Cp and the sum of Ca + Cv. When Po was 6-11 mmHg, Cp was 0.393 +/- 0.0380 (SE) ml X mmHg-1 X kg-1 with forward perfusion and 0.263 +/- 0.0206 (SE) ml X mmHg-1 X kg-1 with reverse perfusion. Calv was 79 and 68% of Cp with forward and reverse perfusion, respectively. When Po was raised to 16-21 mmHg, Cp decreased to 0.225 +/- 0.0235 (SE) ml X mmHg-1 X kg-1 and 0.183 +/- 0.0133 (SE) ml X mmHg-1 X kg-1 with forward and reverse perfusion, respectively. Calv also decreased but remained the largest contributor to Cp. We conclude that the major site of pulmonary vascular compliance in the canine lung is the alveolar compartment, with minor contributions from the arterial and venous extra-alveolar segments.