Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p < or = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at > or =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.

Regional hypoxic pulmonary vasoconstriction in prone pigs.

Hypoxic pulmonary vasoconstriction (HPV) is known to affect regional pulmonary blood flow distribution. It is unknown whether lungs with well-matched ventilation (V)/perfusion (Q) have regional differences in the HPV response. Five prone pigs were anesthetized and mechanically ventilated (positive end-expiratory pressure = 2 cmH2O). Two hypoxic preconditions [inspired oxygen fraction (FI(O2)) = 0.13] were completed to stabilize the animal's hypoxic response. Regional pulmonary blood Q and V distribution was determined at various FI(O2) (0.21, 0.15, 0.13, 0.11, 0.09) using the fluorescent microsphere technique. Q and V in the lungs were quantified within 2-cm3 lung pieces. Pieces were grouped, or clustered, based on the changes in blood flow when subjected to increasing hypoxia. Unique patterns of Q response to hypoxia were seen within and across animals. The three main patterns (clusters) showed little initial difference in V/Q matching at room air where the mean V/Q range was 0.92-1.06. The clusters were spatially located in cranial, central, and caudal portions of the lung. With decreasing FI(O2), blood flow shifted from the cranial to caudal regions. We determined that pulmonary blood flow changes, caused by HPV, produced distinct response patterns that were seen in similar regions across our prone porcine model.

Determination of regional ventilation and perfusion in the lung using xenon and computed tomography.

We propose a model to measure both regional ventilation (V) and perfusion (Q) in which the regional radiodensity (RD) in the lung during xenon (Xe) washin is a function of regional V (increasing RD) and Q (decreasing RD). We studied five anesthetized, paralyzed, mechanically ventilated, supine sheep. Four 2.5-mm-thick computed tomography (CT) images were simultaneously acquired immediately cephalad to the diaphragm at end inspiration for each breath during 3 min of Xe breathing. Observed changes in RD during Xe washin were used to determine regional V and Q. For 16 mm(3), Q displayed more variance than V: the coefficient of variance of Q (CV(Q)) = 1.58 +/- 0.23, the CV of V (CV(V)) = 0.46 +/- 0.07, and the ratio of CV(Q) to CV(V) = 3.5 +/- 1.1. CV(Q) (1.21 +/- 0.37) and the ratio of CV(Q) to CV(V) (2.4 +/- 1.2) were smaller at 1,000-mm(3) scale, but CV(V) (0.53 +/- 0.09) was not. V/Q distributions also displayed scale dependence: log SD of V and log SD of Q were 0.79 +/- 0.05 and 0.85 +/- 0.10 for 16-mm(3) and 0.69 +/- 0.20 and 0.67 +/- 0.10 for 1,000-mm(3) regions of lung, respectively. V and Q measurements made with CT and Xe also demonstrate vertically oriented and isogravitational heterogeneity, which are described using other methodologies. Sequential images acquired by CT during Xe breathing can be used to determine both regional V and Q noninvasively with high spatial resolution.

Isocapnic hyperventilation increases carbon monoxide elimination and oxygen delivery.

Hyperventilation with mixtures of O2 and CO2 has long been known to enhance carbon monoxide (CO) elimination at low HbCO levels in animals and humans. The effect of this therapy on oxygen delivery (DO2) has not been studied. Isocapnic hyperventilation utilizing mechanical ventilation may decrease cardiac output and therefore decrease DO2 while increasing CO elimination. We studied the effects of isocapnic hyperventilation on five adult mechanically ventilated sheep exposed to multiple episodes of severe CO poisoning. Five ventilatory patterns were studied: baseline minute ventilation (RR. VT), twice (2. RR) and four times (4. RR) baseline respiratory rate, and twice (2. VT) and four times (4. VT) baseline tidal volume. The mean carboxyhemoglobin (HbCO) washout half-time (t1/2) was 14.3 +/- 1.6 min for RR. VT, decreasing to 9.5 +/- 0.9 min for 2. RR, 8.0 +/- 0.5 min for 2. VT, 6.2 +/- 0.5 min for 4. RR, and 5.2 +/- 0.5 min for 4. VT. DO2 was increased during hyperventilation compared with baseline ventilation for 2. VT, 4. RR, and 4. VT ventilatory patterns. Isocapnic hyperventilation, in our animal model, did not alter arterial or pulmonary blood pressures, arterial pH, or cardiac output. Isocapnic hyperventilation is a promising therapy for CO poisoning.

Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI.

Allergen-induced asthma is characterized by chronic pulmonary inflammation, reversible bronchoconstriction, and airway hyperreactivity to provocative stimuli. Multiple CC-chemokines, which are produced by pulmonary tissue in response to local allergen challenge of asthmatic patients or experimentally sensitized rodents, chemoattract leukocytes from the circulation into the lung parenchyma and airway, and may also modify nonchemotactic function. To determine the therapeutic potential of local intrapulmonary CC-chemokine blockade to modify asthma, a recombinant poxvirus-derived viral CC-chemokine inhibitor protein (vCCI), which binds with high affinity to rodent and human CC-chemokines in vitro and neutralizes their biological activity, was administered by the intranasal route. Administration of vCCI to the respiratory tract resulted in dramatically improved pulmonary physiological function and decreased inflammation of the airway and the lung parenchyma. In contrast, vCCI had no significant effect on the circulating levels of total or allergen-specific IgE, allergen-specific cytokine production by peripheral lymph node T cells, or peritoneal inflammation after local allergen challenge, indicating that vCCI did not alter systemic Ag-specific immunity or chemoattraction at extrapulmonary sites. Together, these findings emphasize the importance of intrapulmonary CC-chemokines in the pathogenesis of asthma, and the therapeutic potential of generic and local CC-chemokine blockade for this and other chronic diseases in which CC-chemokines are locally produced.

Selected contribution: redistribution of pulmonary perfusion during weightlessness and increased gravity.

To compare the relative contributions of gravity and vascular structure to the distribution of pulmonary blood flow, we flew with pigs on the National Aeronautics and Space Administration KC-135 aircraft. A series of parabolas created alternating weightlessness and 1.8-G conditions. Fluorescent microspheres of varying colors were injected into the pulmonary circulation to mark regional blood flow during different postural and gravitational conditions. The lungs were subsequently removed, air dried, and sectioned into approximately 2 cm(3) pieces. Flow to each piece was determined for the different conditions. Perfusion heterogeneity did not change significantly during weightlessness compared with normal and increased gravitational forces. Regional blood flow to each lung piece changed little despite alterations in posture and gravitational forces. With the use of multiple stepwise linear regression, the contributions of gravity and vascular structure to regional perfusion were separated. We conclude that both gravity and the geometry of the pulmonary vascular tree influence regional pulmonary blood flow. However, the structure of the vascular tree is the primary determinant of regional perfusion in these animals.

Hemodynamic effects of 15-microm-diameter microspheres on the rat pulmonary circulation.

The microsphere method has been used extensively to measure regional blood flow in large laboratory animals. A fundamental premise of the method is that microspheres do not alter regional flow or vascular tone. Whereas this assumption is accepted in large animals, it may not be valid in the pulmonary circulation of smaller animals. Three studies were performed to determine the hemodynamic effects of microspheres on the rat pulmonary circulation. Increasing numbers of 15-microm-diameter microspheres were injected into a fully dilated, isolated-lung preparation. Vascular resistance increased 0.8% for every 100,000 microspheres injected. Microspheres were also injected into an isolated-lung preparation in which vascular tone was increased with hypoxia. Microspheres did not induce vasodilatation, as reported in other vascular beds. Fluorescent microspheres were injected via tail veins into awake rats, and the spatial locations of the microspheres were determined. Regional distributions remained highly correlated when microspheres of one color were injected after microspheres of another color. This indicates that the initial injection did not alter regional perfusion. We conclude that, when used in appropriate numbers, 15-microm-diameter microspheres do not alter regional flow or vascular tone in the rat pulmonary circulation.

Effect of zonal conditions and posture on pulmonary blood flow distribution to subpleural and interior lung.

Observations made on vessels seen directly beneath the pleura may not accurately reflect what occurs in vessels located deeper in the interior of the lung. We quantified flow to subpleural and deeper, interior regions under zone 1 or 2 conditions in excised (n = 5) and in vivo (n = 6) rabbit lungs, in the head-up or inverted position. After infusion of radiolabeled microspheres, lungs were dried at alveolar pressure of 25 cmH(2)O and sliced in 1-cm sections along the gravitational plane and in three planes in the dorsal-ventral axis. Regions located <1 mm from the pleural surface were dissected away from the remaining tissue. In both zonal conditions, 1) weight-normalized flow to the interior exceeded that found in subpleural regions; and 2) flow followed the gravitational gradient, with the correlation varying with the scale of measurement. We conclude that flow through subpleural vessels is less than that which occurs deeper in the interior, but the regional distributions of flow and the effects of zonal conditions are similar in the two regions.

The role of the inhibitory nonadrenergic noncholinergic system in antigen-induced pulmonary hypersensitivity.

To study the role of the inhibitory nonadrenergic noncholinergic (i-NANC) system in regulating bronchial reactivity during antigen challenge, we first tested a blocker of the i-NANC system (oxyhemoglobin, HbO2, 2.5 microm) on the relaxation response of guinea pig tracheal strips (n=6) in vitro to electrical field stimulation (ES) in the presence of atropine (1 microg/ml) and propranolol (2 microg/ml). Fresh HbO2 significantly inhibited 35.3+/-4.5% (P<0.001) of the NANC relaxation response. Secondary, 26 anesthetized, ovalbumin-sensitized animals were divided into three groups: antigen challenged (n=10), pretreated with HbO2 (13 mg/kg) and challenged (n=9), and treated with HbO2 only (n=7). Pulmonary resistance (RL) and dynamic compliance (Cdyn) were measured 15-20 min prior to (baseline) and up to 30 min after antigen or HbO2 injection. Antigen challenge alone induced early maximal respiratory changes: RL increased 1646+/-115% above baseline (2 min) whereas Cdyn decreased 42+/-10% below baseline (4 min). These changes returned to baseline within 15 min. Pretreatment with HbO2 increased peak respiratory responses induced by antigen [RL, 3728+/-1680% above baseline; Cdyn, 69+/-7% below baseline (P<0.05)]. HbO2 delayed significantly (P<0.05) the time for recovery of RL and Cdyn. HbO2 alone had little effect on respiratory parameters. We conclude that HbO2 may antagonize the i-NANC system in the airway and this antagonism may accentuate pulmonary hypersensitivity during acute antigen challenge.

Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response.

We used various ovalbumin sensitization and challenge protocols to determine the importance of the route of allergen administration and the genetic background in modulating the physiologic, inflammatory, and immunologic features characteristic of allergen-induced asthma. In BALB/c mice, induction of maximal airway hyperresponsiveness and airspace eosinophilia required administration of ovalbumin by both the intraperitoneal and the intranasal routes (combination protocol), whereas intraperitoneal immunization alone resulted in maximal ovalbumin-specific IgE plasma levels. Thus, a systemic immune response to allergen, in addition to, or independent of IgE production, as well as local allergen challenge were necessary for maximal induction of pulmonary disease. BALB/c mice treated with ovalbumin by the combination protocol had increased Th2-type cytokine mRNA levels in bronchial lymph node tissue compared with control mice. In contrast, C57BL/6 mice treated with ovalbumin by the combination protocol had significantly decreased responses compared with BALB/c mice for all parameters of allergic pulmonary disease examined, with the exception of airspace eosinophilia. Genetic background has a striking and selective effect on the phenotype of murine allergic pulmonary disease. Further analysis of this murine model should be useful in helping define the critical pathogenetic events in allergen-induced asthma.

Comparison of five measures derived from in vivo pulmonary vascular pressure-flow curves.

In order to facilitate evaluation of acute changes in lung vascular characteristics in vivo, pressure-flow (delta P-Q) curves of the pulmonary circulation were obtained by step-wise flow reduction. A balloon-tipped Swan-Ganz catheter was inserted via the jugular vein into the inferior vena cava of anesthetized, open chest, ventilated rabbits. Pulmonary arterial (Ppa) and left atrial (Pla) pressures were measured via catheters, and cardiac output Q by an electromagnetic flow probe on the aorta. Inflation of the balloon for 10 s reduced Q by 30-70%. delta P-Q curves were constructed by plotting a series of values of Q against corresponding delta P (= Ppa-Pla). To evaluate the feasibility and sensitivity of the method, these curves were compared under three conditions each paired with control (normoxia): hypoxia (8% O2), isoproterenol infusion, and serotonin infusion. Within our measured flow ranges, most delta P-Q plots were fairly linear, and extrapolated to a positive delta P intercept. Comparing slope, intercept, resistance, delta P at fixed Q, and Q at fixed delta P, we found that the latter two provided the more sensitive index to differentiate vasomotor changes. Since delta P-Q curves generally miss the origin, calculated pulmonary vascular resistance must depend on Q. Therefore, using the shifts in entire delta P-Q curves to select common range of Q and/or delta P is in general more quantitatively reliable for defining altered vascular characteristics.

Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.

The importance of leukotrienes in airway inflammation in a mouse model of asthma.

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.

Effects of exogenous surfactant on lung pressure-volume characteristics during liquid ventilation.

Total liquid ventilation (LV) lowers airway pressures and potentially reduces barotrauma in models of hyaline membrane disease. LV eliminates surface tension by eliminating the air-perfluorochemicals (PFC) interface but does not eliminate interfacial tension (IT) at the lung/PFC interface. We hypothesized that pretreatment with exogenous surfactant before LV would shift the overall pressure-volume (PV) curve to the left, compared with LV without surfactant. Sequential quasi-static PV curves were obtained in 10 excised lungs (saline, air, PFC), with one-half randomized to exogenous surfactant replacement before LV. Analysis revealed that maximal inflation pressures were reduced during LV compared with baseline air curves. Addition of exogenous surfactant to LV further reduced maximal inflation pressures. A novel approach was used to transform these PV curves to estimates of in situ IT-volume curves. Estimated maximal IT at 20 ml/kg in preterm lamb lungs on air inflation after surfactant was 51 mN/m, compared with 40 mN/m for LV alone and with 27 mN/m for the combination of surfactant and LV. We conclude that the IT-reducing properties of the PFC studied (perflubron) can be augmented through the use of exogenous surfactant.

Airway hyperreactivity is associated with specific leukocyte subset infiltration in a mouse model of allergic airway inflammation.

Airway hyperreactivity is defined as an increased bronchoconstrictor response to physical, pharmacological, or other stimuli. Patients with asthma develop airway hyperreactivity as well as peribronchial inflammation. We employed an established schistosome soluble egg antigen (SEA)-induced murine model of allergic inflammation to examine the temporal relationship between airway hyperreactivity and leukocyte subset infiltration. Dose response curves of intravenous methacholine were used in mice to characterize airway reactivity at various time points after intranasal SEA rechallenge. Cellular infiltration into the airspace was assessed by bronchoalveolar lavage. Airway hyperreactivity increased as early as 1 h postchallenge. Peak hyperreactivity occurred at 8 h postchallenge. Subsequently, reactivity decreased at 24 h and fell to the level observed in controls by 48 h. Neutrophil influx correlated directly with the increase in airway reactivity, as neutrophils were observed as early as 1 h, peaked at 8 h, diminished by 24 h and were not detected at 48 h post-SEA challenge. In contrast, eosinophil infiltration was not observed until 24 h and peaked at 48 h post-SEA rechallenge when increases in airway reactivity were not detected. Airway resistance induced by methacholine correlated with neutrophil (r2 = 0.90) but not eosinophil (r2 = 0.1) infiltration. These results suggest that the airway hyperreactivity observed during allergic airway inflammation correlates with airways neutrophilia and weakly eosinophil accumulation.

Perfusion through vessels open in zone 1 contributes to gas exchange in rabbit lungs in situ.

We previously found that up to 15% of the normal cardiac output can flow through lungs that are entirely in zone 1 and that the zone 1 pathway utilizes alveolar corner vessels. Because of the proximity of these vessels to alveoli, we hypothesized that lungs perfused under zone 1 conditions would exchange gas. We used the multiple inert gas elimination technique to assess the ventilation-perfusion (VA/Q) distribution under zones 1 and 2 in six rabbit lungs perfused with tris(hydroxymethyl)aminomethane-buffered Tyrode solution containing 1% albumin, 4% dextran, and papaverine (25 mg/l). High-frequency oscillation (tidal volume = 2.8 ml at 20 Hz, bias flow = 1 l/min) kept alveolar pressure (PA) nearly constant at 10 or 20 cmH2O. Pulmonary arterial pressure was set 2.5 cmH2O below or 5 cmH2O above PA (zones 1 and 2, respectively). Pulmonary venous pressure was kept at 0 cmH2O, with zero reference being the bottom of the lung. At PA of 10 cmH2O, flow was 64 +/- 40 and 5 +/- 3 ml/min (P < 0.05) and the mean VA/Q for perfusion was 1.1 +/- 0.4 and > 5 (P < 0.05) in zones 2 and 1, respectively. At PA of 20 cmH2O, flow was 89 +/- 36 and 22 +/- 13 ml/min (P < 0.05) and the mean VA/Q for perfusion was 0.8 +/- 0.3 and 3.7 +/- 2.4 (P < 0.05) in zones 2 and 1, respectively. Shunt averaged < 5% of total flow in all conditions. Blood flowing through vessels remaining open under zone 1 conditions 1) exchanges gas, 2) does not occur through anatomic or physiological shunts, and 3) may explain the high VA/Q seen with positive end-expiratory pressure.

Flow pulsatility does not increase mean microvascular pressure or filtration in zone 3 rabbit lungs.

We previously reported that mean pulmonary arterial pressure (Ppa) during pulsatile flow exceeded that for steady flow when flow was greater than the normal resting value and speculated that this was due to irregularities of the flow profiles in precapillary vessels, mainly the larger arteries. From this we hypothesized that neither mean microvascular pressure nor the rate of fluid filtration would be affected by flow pulsatility. We therefore compared the effects of steady vs. pulsatile flow on the double-occlusion pressure (Pdo) and on edema formation (rate of weight gain) in zone 3 rabbit lungs. Excised left lungs (n = 19) were perfused with Tyrode solution and ventilated with an end-expiratory pressure of 2.5 cmH2O. A diaphragm pump generated pulsatile flow with a stroke volume of 1.0 ml (approximately 0.8 the normal resting value for rabbit left lung). Nonpulsatile flow was generated by raising an arterial reservoir. Flow rate was set at 100 or 400 ml/min (approximately 0.4 or 1.6 x the normal resting cardiac output, respectively). Vascular pressures (referenced to the bottom of the lung) were measured after ventilation, at end expiration, was interrupted. Pdo values were obtained in random order at 15 time points that were evenly distributed within the pulse cycle, averaged across pulses to obtain the mean capillary pressure profile, and then averaged over time. At the lower flow of 100 ml/min, mean Ppa and Pdo were slightly lower (3-4%) during pulsatile compared with nonpulsatile conditions. At the higher flow of 400 ml/min, mean Ppa was higher under pulsatile conditions (13%), whereas downstream the mean Pdo values were equal.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism by which the prone position improves oxygenation in acute lung injury.

The mechanism by which oxygenation improves when patients with ARDS are turned from supine to prone position is not known. From results of our previous studies we reasoned that (1) when supine, in the setting of lung injury, transpulmonary pressure will be less than airway opening pressure and (2) atelectasis will develop preferentially in dorsal lung areas, and (3) both ventilation and ventilation/perfusion ratios would improve in these regions on turning prone. To study this directly, we measured regional ventilation and perfusion using 81mKr and 99mTc-MAA, respectively, and single photon emission computed tomography, both prone and supine, in four control animals and four given oleic acid. After oleic acid, the prone position improved (1) oxygenation (mean +/- SD PaO2 = 140 +/- 112 versus 453 +/- 54 mm Hg), (2) median ventilation/perfusion ratios (0.77 versus 0.95), (3) ventilation/perfusion heterogeneity (coefficient of variation 86 +/- 15 versus 61 +/- 6), and (4) the gravitational ventilation/perfusion gradient (dependent to non-dependent slopes of 0.22 versus -0.02, all p < 0.05). The prone position generates a transpulmonary pressure sufficient to exceed airway opening pressure in dorsal lung regions, i.e., in regions where atelectasis, shunt, and ventilation/perfusion heterogeneity are most severe, without adversely affecting ventral lung regions.

Pulsatile and nonpulsatile pressure-flow relationships in zone 3 excised rabbit lungs.

We compared the effects of pulsatile vs. nonpulsatile flow (Q) on pulmonary arterial pressure (Ppa)-Q relationships in zone 3 over wide ranges of pulse rate, stroke volume (SV), and Q. Excised left lungs of rabbits (n = 15) were perfused with tris(hydroxymethyl)aminomethane-buffered Tyrode solution containing 4% dextran, 1% albumin, and 10 mg/l of indomethacin and were ventilated with room air. Pulsatile Q was generated by a diaphragm pump delivering SV of 0.5, 1, or 2 ml (representing approximately 0.3, 0.6, and 1.2 times, respectively, the normal resting SV for rabbit left lung) and adjusting the pump frequency. Nonpulsatile Q was generated by raising an arterial reservoir to the required height. Mean pulmonary arterial (Ppa) and left atrial pressures were measured at end exhalation (positive end-expiratory pressure = 2.5 cmH2O) near the tips of the perfusion cannulas and were referenced to the lung base. Left atrial pressure was held constant at 7 cmH2O.Q was alternated between pulsatile and nonpulsatile, increasing Q stepwise from 100 to 600 ml/min (Q from approximately 0.3 to 2 times the normal resting Q for rabbit left lung), after which Q was reduced stepwise back to initial values. For the smallest SV there were no differences between Ppa-Q curves under pulsatile and nonpulsatile conditions. At the largest SV, Ppa was greater during pulsatile than nonpulsatile Q at Q > 100 ml/min. The slopes of the Ppa-Q curves were greater during pulsatile Q at the two larger SV values. These results can be explained by increasing Q turbulence and less ideal velocity profiles at higher peak Q resulting from the effects of rapidly changing inertial forces.

Lung inflation distends small arteries (< 1 mm) in excised dog lungs.

We utilized microfocal fluoroscopic angiography to study the influence of lung inflation on small (0.2- to 1.3-mm-diam) pulmonary arteries in isolated left lower lobes from dog lungs during both flow and no-flow conditions. Alveolar pressure, which in this preparation was equal to transpulmonary pressure, was set at 2, 8, or 14 mmHg while vascular pressure was varied from 0 to 24 mmHg. The diameters of these small arterial vessels increased with lung inflation. No differences were observed between the results obtained during flow and no-flow conditions. Thus, arteries in this diameter range can be considered as extra-alveolar, and the effect of lung inflation on these small extra-alveolar arteries was qualitatively similar to that previously described for larger extra-alveolar vessels. Quantitatively, the degree of vessel distension was about the same per unit increase in transpulmonary pressure at constant vascular pressure as for a change in vascular pressure at constant transpulmonary pressure. Accordingly, inflation produced a decrease in perivascular pressure surrounding these small arteries that was approximately equal to the increase in transpulmonary pressure.