Differences and similarities between human and rabbit neutrophil granulocyte responses in vitro: the effects of zymosan-activated plasma, phorbol myristate acetate and n-formyl-methionyl-leucyl-phenylalanine

The amount of reactive oxygen intermediates (ROI) generated by activated polymorphonuclear neutrophils (PMN), as well as the closeness of contact between PMN and vessel wall, may determine whether PMN activators will induce the adult respiratory distress syndrome. We examined the ROI-generating and aggregating effects of zymosan activated plasma (ZAP), phorbol myristate acetate (PMA) and n-formyl-methionyl-leucyl-phenylalanine (FMLP), on isolated human and rabbit PMN. PMA, after a short lag phase, induced a large and long-lasting increase in ROI generation. The initial peak response was higher and more rapid in human than in rabbit cells. The reaction to FMLP occurred almost instantaneously, but was much weaker than that to PMA, and ROI generation returned to near baseline in less than 10 min. No species difference was seen. ZAP caused an FMLP-like ROI response in human cells, whereas no response was observed in rabbit PMN. PMN aggregation was induced by all three activators, most markedly by PMA. No species difference was detected for PMA; FMLP gave a stronger aggregation of rabbit than of human PMN, however, while the opposite was true for ZAP. In conclusion, ZAP was a potent stimulus for PMN aggregation, but had modest (or no) effects on the production of ROI. Marked differences between human and rabbit PMN responses were observed.     

Effects of high dose E. coli lipopolysaccharide on rabbit lung function,and of subsequent addition of chemotactic granulocyte activators to their isolated,blood-perfused lungs

E. coli LPS was infused (1 μg/kg to 5 mg/kg over 30 min) to spontaneously breathing rabbits, and their arterial blood pressure (ABP), blood leukocyte count and blood gases were observed for 2.5–3.5 h. Pulmonary vascular and airway function were subsequently evaluated in vitro by comparing weight changes, fluid filtration rates, pulmonary vascular resistance (PVR) and airway pressures in their isolated, blood-perfused lungs with those in lungs from untreated rabbits. Lung preparations from both groups of animals were then exposed to autologous zymosan-activated plasma (ZAP) or n-formyl-methionyl-leucyl-phenylalanine (FMLP) and perfused for 2 more hours. LPS addition to isolated rabbit leukocytes increased cell aggregation; cell chemiluminescence after activation with FMLP was also enhanced. Infusion of 1–5 mg/kg LPS decreased the count of all types of leukocytes and caused a metabolic acidosis (BE< –8 mmol), but no decrease in ABP. PAo₂-Pao₂ increased by about 2.0 kPa. No vascular permeability increase was detected in the lungs of these animals during subsequent in vitro perfusion. Addition of ZAP or FMLP during perfusion markedly increased the PVR in lungs from LPS animals, but did not induce major microvascular leakage. No significant differences in edema between lungs from LPS-treated and control animals were found by microscopy.     

烧伤后粘附分子介导中性粒细胞粘附对肺血管通透性的影响

目的观察比较烧伤血清及烧伤后中性白细胞（ＰＭＮ）对肺血管通透性的影响,分析ＰＭＮ粘附及粘附分子ＣＤ１１ｂ／ＣＤ１８在该影响中的介导作用。方法应用离体肺灌流技术,通过肺重量增加（ＬＷＧ）、液体滤过系数（Ｋｆ）和通透性表面积乘积（ＰＳ）分别观察肺水肿程度、肺血管对小分子物质和大分子物质的通透性。结果烧伤血清能使ＬＷＧ、Ｋｆ和ＰＳ明显增加,以Ｋｆ增加最为明显;烧伤后ＰＭＮ也能使Ｋｆ和ＰＳ增加,以ＰＳ增加为明显;用单抗封闭烧伤后ＰＭＮ膜上ＣＤ１１ｂ／ＣＤ１８后,ＰＭＮ在肺血管内的滞留减少,Ｋｆ和ＰＳ值增加被抑制,并以ＰＳ改变为显著。结论（１）被激活的ＰＭＮ释放的介质类物质如氧自由基、蛋白酶等物质对肺微血管内皮细胞（ＰＭＥＣ）的损伤作用部分依赖于ＰＭＮ与内皮细胞的粘附。（２）烧伤后被激活的ＰＭＮ释放的介质类物质主要介导肺血管对小分子物质通透性的影响。烧伤后ＰＭＮ与肺微血管内皮细胞（ＰＭＥＣ）的粘附除了使介质类物质的作用放大外,还介导肺血管对大分子物质通透作用。（３）ＰＭＮ膜上ＣＤ１１ｂ／ＣＤ１８分子可能通过与ＰＭＥＣ细胞间粘附分子的结合,本身具有对内皮细胞的生物学调控作用     

Superoxide anion mediates pulmonary vascular permeability caused by neutrophils in cardiopulmonary bypass

During cardiopulmonary bypass (CPB), neutrophils (PMNs) may be stimulated by shear stress which could contribute to the pulmonary injury that occurs after CPB. To elucidate whether mechanically stimulated PMNs increase pulmonary vascular permeability, measured as the pulmonary filtration coefficient (K) and pulmonary vascular resistance, and to elucidate whether superoxide anion mediates this increase, we assessed the effects of stimulated and unstimulated PMNs, and of superoxide dismutase (SOD) on K and resistance in isolated perfused lungs from Sprague-Dawley rats. PMNs were stimulated by gentle agitation in a glass vial for 10s. Lungs perfused with the stimulated PMNs, being the stimulated group (n=6), elicited a 5-fold increase in the filtration coefficient compared with lungs perfused with unstimulated cells, being the unstimulated group (n=6). This increase in filtration was completely blocked by the pre-incubation of stimulated PMNs with CD18 monoclonal antibody, being the Ab group (n=6), and also by superoxide dismutase, being the SOD group (n=6). Pulmonary vascular resistance was not increased by stimulated PMNs, and the accumulation of stimulated PMNs was not blocked by SOD. These findings suggest that stimulated PMNs increaseK and that superoxide anion may injure the pulmonary vascular endothelial cells.     

Phenotypic heterogeneity in lung capillary and extra-alveolar endothelial cells. Increased extra-alveolar endothelial permeability is sufficient to decrease compliance

BACKGROUND: In acute respiratory distress syndrome, pulmonary vascular permeability increases, causing intravascular fluid and protein to move into the lung's interstitium. The classic model describing the formation of pulmonary edema suggests that fluid crossing the capillary endothelium is drawn by negative interstitial pressure into the potential space surrounding extra-alveolar vessels and, as interstitial pressure builds, is forced into the alveolar air space. However, the validity of this model is challenged by animal models of acute lung injury in which extra-alveolar vessels are more permeable than capillaries under a variety of conditions. In the current study, we sought to determine whether extravascular fluid accumulation can be produced because of increased permeability of either the capillary or extra-alveolar endothelium, and whether different pathophysiology results from such site-specific increases in permeability. MATERIALS AND METHODS: We perfused isolated lungs with either the plant alkaloid thapsigargin, which increases extra-alveolar endothelial permeability, or with 4alpha-phorbol 12, 13-didecanoate, which increases capillary endothelial permeability. RESULTS: Both treatments produced equal increases in whole lung vascular permeability, but caused fluid accumulations in separate anatomical compartments. Light microscopy of isolated lungs showed that thapsigargin caused fluid cuffing of large vessels, while 4alpha-phorbol 12, 13-didecanoate caused alveolar flooding. Dynamic compliance was reduced in lungs with cuffing of large vessels, but not in lungs with alveolar flooding. CONCLUSIONS: Phenotypic differences between vascular segments resulted in site-specific increases in permeability, which have different pathophysiological outcomes. Our findings suggest that insults leading to acute respiratory distress syndrome may increase permeability in extra-alveolar or capillary vascular segments, resulting in different pathophysiological sequela.     

Prediction of transplant outcome after 24‐hour ex vivo lung perfusion using the Organ Care System in a porcine lung transplantation model

Ex vivo lung perfusion (EVLP) has become routine practice in lung transplantation. Still, running periods exceeding 12 hours have not been undertaken clinically to date, and it remains unclear how the perfusion solution for extended running periods should be composed and which parameters may predict outcomes. Twenty‐four porcine lungs underwent EVLP for 24 hours using the Organ Care System (OCS). Lungs were ventilated and perfused with STEEN's solution enriched with erythrocytes (n = 8), acellular STEEN's solution (n = 8), or low‐potassium dextran (LPD) solution enriched with erythrocytes (n = 8). After 24 hours, the left lungs were transplanted into recipient pigs. After clamping of the contralateral lung, the recipients were observed for 6 hours. The most favorable outcome was observed in organs utilizing STEEN solution enriched with erythrocytes as perfusate, whereas the least favorable outcome was seen with LPD solution enriched with erythrocytes for perfusion. Animals surviving the observation period showed lower peak airway pressure (PAWP) and pulmonary vascular resistance (PVR) during OCS preservation. The results suggest that transplantation of lungs following 24 hours of EVLP is feasible but dependent on the composition of the perfusate. PAWP and PVR during EVLP are early and late predictors of transplant outcome, respectively.     

Triolein increases microvascular permeability in isolated perfused rabbit lungs: role of neutrophils

BACKGROUND: Pathophysiologic mechanisms of the fat embolism syndrome are poorly understood. Neutrophils are thought to play a role in the development of many forms of acute lung injury. The objective of this study was to examine the role of intrapulmonary neutrophils in lung injury resulting from fat infusion. METHODS: Triolein (0.08 mL/kg) was infused into isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pulmonary arterial pressure was monitored, and pulmonary vascular resistance and microvascular permeability (Kf) were measured at baseline and 60 minutes after triolein infusion. RESULTS: Triolein produced increases in pulmonary arterial pressure, pulmonary vascular resistance, and Kf. Neutrophil depletion or inhibition of neutrophil elastase prevented the increase in Kf after triolein, and catalase partially blocked this Kf increase. CONCLUSION: These results suggest that activated intrapulmonary neutrophils play a major role in developing triolein-induced lung injury, intrapulmonary neutrophils act chiefly via neutrophil elastase release, and reactive oxygen species are involved in the lung injury.     

Vascular Resistance in Atelectatic Lungs: Effects of Inhalation Anesthetics

We have investigated the relative contribution of mechanical obstruction and hypoxia-induced vasoconstriction to the increased pulmonary vascular resistance (PVR) in atelectatic lungs. For this purpose we have utilized the previous observation that inhalation anesthetics inhibit the vasoconstrictor response to pulmonary hypoxia. The effects of halothane. enfluranr and ether on PVR in atelectatic lungs have been explored. Two pairs of isolated rat lung were perfused in series at constant flow. One of the preparations was made atelectatic by airway occlusion subsequent to ventilation with a high Po₂ gas (95% 02). Ventilation of the other preparation continued with hypoxic gas (2% 02). resulting in a gradual increase in PVR in both preparations. When maximum PVR was reached, one of the above inhalation anesthetics was administered to the atelectatic lungs via the ventilated lung preparation. This caused a dose-dependent, reversible reduction of PVR. The same effect was observed when pulmonary arterial PQ was increased (>66.5kPa). Histological examination revealed that two out of four preparations were completely atelectatic I h after airway occlusion, whereas atelectasis was nearly complete in the other two. In two groups, airways were occluded for 1 h. In the first group PVR increased to 163% (median) above baseline level, as found during ventilation with high PO2. High arterial Po2 reduced PVR in the atelectatic lungs to 50% (median) above baseline, whereas papaverine induced a further PVR reduction. to 7% (median) above baseline. In the other group, papaverine was given before airway occlusion, and PVR increased to 10% (median) above baseline. Comparison of the two groups shows that mechanical Obstruction accounts for about 6% (10/163) of the overall rise in PVR during atelectasis.     

Role of inhaled nitric oxide in ischaemia-reperfusion injury in the perfused rabbit lung

We have tested if inhaled nitric oxide (NO) is beneficial in ischaemia- reperfusion (IR) lung injury using an isolated perfused rabbit lung model. Ischaemia for 60 min was followed by reperfusion and ventilation with nitric oxide 40 ppm (n = 6) or without nitric oxide ventilation (n = 6) for 60 min. In the control group (n = 6), the lungs were perfused continuously for 120 min. Permeability coefficient (Kfc) and vascular resistance (PVR) were measured serially for 60 min after reperfusion. We also determined the left lung W/D ratio and measured nitric oxide metabolites (NOx) and cGMP concentrations in bronchoalveolar lavage (BAL) fluid from the right lung. IR increased Kfc, PVR and W/D followed by decreased cGMP. Ventilation with nitric oxide restored these changes by preventing the decrease in cGMP. Differences in NOx concentrations in BAL fluid between the control and IR groups were not statistically significant. Our results indicate that IR impaired pulmonary vascular function and resulted in microvascular constriction and leakage. Ventilation with nitric oxide from the beginning of the reperfusion period improved pulmonary dysfunction such as vasoconstriction and capillary leak by restoring cGMP concentrations.      

A thromboxane analog increases pulmonary capillary pressure but not permeability in the perfused rabbit lung

Thromboxane has been implicated as a mediator of pulmonary hypertension and pulmonary edema in acute respiratory failure. Pulmonary edema may result from increased pulmonary capillary hydrostatic pressure or from increased pulmonary vascular permeability. We therefore studied the effects of a stable thromboxane analog, U46619, on these two parameters in the perfused rabbit lung. Pulmonary capillary pressure was measured by the double vascular occlusion method, and pulmonary vascular permeability was estimated by measurement of the pulmonary fluid filtration coefficient (Kf). U46619 infusion produced pulmonary hypertension and lung weight gain; increased both the arterial (precapillary) and venous (postcapillary) components of pulmonary vascular resistance; and increased pulmonary capillary pressure from 4.7 +/- 0.5 to 9.0 +/- 0.7 mmHg (P less than 0.01). The isogravimetric pressure (equivalent to the capillary pressure corresponding to no lung weight gain) was 4.0 +/- 0.4 mmHg before U46619 and 4.6 +/- 0.4 mmHg during U46619. Therefore, U46619 significantly increased capillary pressure above isogravimetric pressure and resulted in the development of pulmonary edema. U46619 did not affect vascular permeability as measured by Kf. We conclude that pulmonary venoconstriction resulting in increased pulmonary capillary hydrostatic pressure is the major mechanism by which thromboxane produces pulmonary edema in isolated lungs.     

Adenosine modulates vascular resistance and fluid filtration in isolated rat lungs

In adult respiratory distress syndrome, a major concern is to reduce increments in pulmonary vascular resistance (PVR) and maintain the patency of lung microvessels. We have investigated the effects of adenosine, a potent systemic vasodilator, on PVR and fluid filtration rate (FFR) in isolated blood-perfused rat lungs. The preparations were undamaged or subjected to fat emulsion-induced injury simulating ARDS. In undamaged lungs adenosine caused a significant dose-dependent reduction of hypoxia-induced increases in PVR. Furthermore, the increase in FFR upon elevation of left atrial pressure by 0.77 kPa was significantly hampered by adenosine, 24 nmol.ml-1.min-1. Employing the same rate of infusion, adenosine, in a group of injured preparations, significantly reduced the rise in PVR towards baseline and completely abolished the further increase upon a superimposed injection of serotonin. In another series of preparations with lung injury randomly assigned to an adenosine group and a control group, adenosine significantly reduced FFR. Thus, adenosine, even when infused at low rates, reduced increments in PVR and fluid filtration, both in undamaged and in fat emulsion-injured isolated lungs.     

Triolein-induced pulmonary embolization and increased microvascular permeability in isolated perfused rat lungs.

BACKGROUND: The pathophysiologic mechanism of the fat embolism syndrome is poorly understood. This study was designed to determine the effects of fat emboli on pulmonary vasculature. METHOD: Triolein was infused into isolated rat lungs perfused with Krebs-Henseleit buffer. Pulmonary arterial pressure and microvascular permeability (Kf) were measured at baseline and 20 minutes after the triolein infusion. RESULT: The 99% triolein produced dose-dependent increases in both pulmonary arterial pressure and Kf. The 65% triolein, containing free fatty acid, resulted in a greater increase in Kf. Pretreatment with indomethacin attenuated the increase in Kf after 65% triolein but not after 99% triolein. CONCLUSION: Pure triolein induced mainly embolization in the pulmonary vasculature, and 65% triolein caused embolization and subsequently increased vascular permeability, which are, at least in part, mediated by the action of cyclooxygenase products. Free fatty acids might induce permeability edema by means of a cyclooxygenase-dependent mechanism. We conclude that triolein-induced increases in pulmonary arterial pressure and Kf in isolated rat lungs provides a useful model of acute lung injury by fat embolism.     

Hyperacute lung rejection in the pig-to-human model 4: evidence for complement and antibody independent mechanisms

BACKGROUND: We assessed whether the combination of complement regulation and depletion of xenoreactive antibodies improves the outcome of pulmonary xenografts compared with either strategy alone. METHODS: Lungs from pigs heterozygous (hDAF(+/-)) or homozygous (hDAF(+/+)) for the human decay accelerating factor transgene (hDAF) or their nontransgenic litter mates (hDAF(-/-)) were perfused with heparinized whole human blood. In additional groups, xenoreactive natural antibodies (XNA) were depleted by pig lung perfusion (hDAF(-/-)/AbAbs, hDAF(+/-)/AbAbs) before the experiment. This combined approach was augmented by adding soluble complement receptor 1 (sCR1) to the perfusate in one further group (hDAF(+/-)/AbAbs/sCR1). RESULTS: HDAF(-/-) lungs perfused with unmodified human blood were rejected after 32.5 min (interquartile range, IQR 5 to 210). HDAF(+/-) lungs survived for 90 min (IQR 10 to 161, P = 0.54). Both groups showed a rapid rise in pulmonary vascular resistance (PVR), which is a characteristic feature of hyperacute rejection (HAR). This phenomenon was blunted in the hDAF(+/+) group, although survival (48 min, IQR 14 to 111) was not further prolonged. Antibody depletion (AbAbs) led to a significant increase in survival time (hDAF(-/-)/AbAbs: 315 min, IQR 230 to 427; hDAF(+/-)/AbAbs: 375 min, IQR 154 to 575), reduced PVR and less complement production. Addition of sCR1 reduced complement elaboration but did not further improve survival (200 min, IQR 128 to 580) and surprisingly tended to increase PVR. CONCLUSIONS: Depletion of xenoreactive antibodies is more effective than membrane-bound complement regulation to blunt hyperacute rejection of pulmonary xenografts, but even the combined approach including soluble-phase complement inhibition is not sufficient to reliably prevent organ failure within hours. It therefore seems likely that other factors independent of antibody and complement contribute to HAR in this model.     

Human complement regulatory proteins protect swine lungs from xenogeneic injury

BACKGROUND: Pulmonary xenotransplantation is not possible because of hyperacute lung injury, the pathogenesis of which is unknown. This study evaluates complement-dependent pathways of pulmonary injury during heterologous perfusion of swine lungs. METHODS: Lungs from unmodified swine and swine expressing human decay-accelerating factor and human CD59 (hDAF/hCD59 swine) were perfused with either human plasma or baboon blood. Pulmonary vascular resistance and static pulmonary compliance were measured serially, and swine lung tissue were examined by light microscopy. Complement activation was assessed by serial measurements of baboon plasma C3a-desArg concentrations. RESULTS: Perfusion of unmodified swine lungs with human plasma and baboon blood resulted in hyperacute lung injury within minutes of perfusion. However, function was preserved in swine lungs expressing human decay-accelerating factor and human CD59. In both study groups, xenogeneic perfusion with baboon blood resulted in at least a sevenfold increase in plasma C3a-desArg levels suggesting transient activation of complement. CONCLUSIONS: Lungs from swine expressing human decay-accelerating factor and human CD59 were resistant to injury during perfusion with human plasma and baboon blood, indicating that complement mediated some of the features of xenogeneic acute lung injury.     

Nitric Oxide Ventilation of Rat Lungs from Non‐Heart‐Beating Donors Improves Posttransplant Function

Lungs from non‐heart‐beating donors (NHBDs) would enhance the donor pool. Ex vivo perfusion and ventilation of NHBD lungs allows functional assessment and treatment. Ventilation of rat NHBD lungs with nitric oxide (NO) during ischemia, ex vivo perfusion and after transplant reduced ischemia‐reperfusion injury (IRI) and improved lung function posttransplant. One hour after death, Sprague‐Dawley rats were ventilated for another hour with either 60% O2 or 60% O2/40 ppm NO. Lungs were then flushed with 20‐mL cold Perfadex, stored cold for 1 h, perfused in an ex vivo circuit with Steen solution and warmed to 37°C, ventilated 15 min, perfusion‐cooled to 20°C, then flushed with cold Perfadex and stored cold. The left lung was transplanted and ventilated separately. Recipients were sacrificed after 1 h. NO‐ventilation was associated with significantly reduced wet:dry weight ratio in the ex vivo circuit, better oxygenation, reduced pulmonary vascular resistance, increased lung tissue levels of cGMP, maintained endothelial NOS eNOS, and reduced increases in tumor necrosis factor alpha (TNF‐α) and inducible nitric oxide synthase (iNOS). NO‐ventilation had no effect on MAP kinases or NF‐κB activation. NO administration to NHBDs before and after lung retrieval may improve function of lungs from NHBDs.     

Pulmonary effects of autotransfused blood. A comparison of fresh autologous and stored blood with blood retrieved from the pleural cavity in an in situ lung perfusion model

An in situ pulmonary lobe perfusion model in dogs was used to examine the pulmonary effects of autotransfused blood as compared with fresh and stored blood. Fresh arterial blood was collected in heparin solution from ten dogs and was drained into and collected from the pleural cavity using a commercially available autotransfusion device for continuous filtration. Results of perfusion with autotransfused blood were compared with results of perfusion of blood stored at 4 °C in ACD solution for twenty-four hours in seven dogs and those of perfusion of blood stored for twenty-one days at 4 °C in ACD solution in seven dogs. The fresh and stored blood samples were passed through a standard recipient set filter prior to perfusion.Perfusion with autotransfused blood resulted in a decreased arteriovenous pO₂ gradient as compared with results in control blood, but there was no concomitant elevation in pulmonary vascular resistance (PVR) or endobronchial pressure (P_b) for the autotransfused blood. Stored blood by comparison showed significantly increased PVR and P_b but a progressive decline in A-VpO₂ which was in excess of the level reached by perfusion of autotransfused blood. Fresh blood showed essentially no change in pulmonary functional parameters during perfusion.The great majority of animals whose lungs were perfused with stored blood had microscopic evidence of interstitial pulmonary edema, perivascular hemorrhage, intra-alveolar fluid, and alveolar congestion. Significantly fewer animals showed these changes when lungs were perfused with autotransfused or fresh blood. Wet-dry weight ratios of lung tissue after perfusion indicated significantly higher uptake of water by the lung perfused with stored blood than by those perfused with autotransfused or fresh blood.     

Heme oxygenase does not contribute to control of basal vascular tone in isolated blood-perfused rat lung.

BACKGROUND: Vasoconstriction in pulmonary ischemia-reperfusion injury may involve dysfunction of the physiologic vasodilation of pulmonary arteries. Little is known of the relative importance of heme oxygenase (HO)/carbon monoxide (CO)-dependent vs nitric oxide synthase (NOS)/nitric oxide (NO)-dependent vasodilation of the pulmonary vasculature. We evaluated the significance of HO function on basal pulmonary vascular resistance (PVR) and compared it with the function of NOS. METHODS: Using an isolated blood-perfusion model, lungs of Lewis rats were assigned to 3 groups (n = 6/group). After stabilization, either an inhibitor of HO (tin-protoporphyrin-9 [SnPP-9]) or an inhibitor of NOS (NG-nitro-L-arginine methylester [L-NAME]) was added to the perfusate (50 micromol/liter and 1 mmol/liter as the final concentration, respectively). Lungs receiving saline served as controls. Gas exchange, hemodynamic and respiratory functions and the levels of cyclic 3',5'-guanosine monophosphate (cGMP) in the perfusate were measured. RESULTS: Inhibition of NOS by L-NAME resulted in a significant (p < 0.01) increase in PVR (DeltaPVR: 0.110 +/- 0.012 cm H(2)O/ml. min) within 5 minutes. In contrast, PVR was minimally affected by SnPP-9 (DeltaPVR: 0.005 +/- 0.005 cm H(2)O/ml. min), which was comparable to control lungs (DeltaPVR: 0.012 +/- 0.005 cm H(2)O/ml. min). The level of cGMP in the perfusate 5 minutes after drug application was markedly, but not significantly, lower in the L-NAME group (1.67 +/- 0.74 nmol/liter) when compared with controls (2.69 +/- 0.89 nmol/liter) and SnPP-9-treated lungs (2.65 +/- 0.66 nmol/liter). CONCLUSIONS: NOS but not HO contributes to the control of basal vascular tone in the rat lung.     

Complement-mediated pulmonary edema in sheep

Incubation of plasma with zymosan results in complement activation. Infusion of zymosan-activated plasma (ZAP) into the pulmonary circulation in sheep results in a transient rise in pulmonary vascular resistance, accompanied by hypoxemia. This is associated with production of the vasoactive prostaglandin metabolite, thromboxane. We hypothesized that ZAP infusion caused pulmonary edema and may transiently alter pulmonary permeability to protein. Two sets of experiments were conducted involving six sheep. Three sheep underwent open lung biopsies during ZAP infusion, and electron microscopy documented early reversible interstitial pulmonary edema in response to ZAP infusion. Three other sheep were prepared with lung lymph fistulae and subjected to a similar infusion of ZAP. These studies documented a rapid rise in lymph flow and lymph protein clearance, occurring immediately upon infusion of ZAP. These experiments demonstrate a rapid reversible interstitial edema in sheep lung in response to ZAP infusion and suggest that permeability to protein may be transiently altered as a result of this injury.     

Oxygen toxicity in normal and anoxic ventilated perfused canine lungs.

Oxygen toxicity was studied in 26 canine isolated, perfused lung lobes which included nine control lobes, 13 lungs ventilated with FIO2 1.0 for 4 hours, and four lobes ventilated with FIN2 1.0 for 1 hour prior to 4 hours of FIO2 1.0 to evaluate the postulated protective effect of anoxia. A significant increase in wet weight was seen in the O2 ventilated lungs which did not alter pulmonary capillary isogravimetric pressure (PCI), alveolar-arterial oxygen gradient, or pulmonary vascular resistance. In contrast, preliminary N2 ventilation resulted in a significant increase in PCI and greater weight gain while pulmonary vascular resistance was reduced. Pulmonary compliance was reduced minimally in all groups. Anoxic ventilation not only failed to protect the isolated canine lung from presumed increased capillary permeability of oxygen toxicity, but seemed to contribute to the formation of interstitial pulmonary edema.     

Hypoxic Pulmonary Vasoconstriction in the Human Lung: the Effect of Prolonged Unilateral Hypoxic Challenge during Anaesthesia

The influence of time on the pulmonary vasoconstrictor response to hypoxia was studied in six subjects during general anaesthesia and artificial ventilation prior to elective surgery. The lungs were intubated separately with a double-lumen bronchial catheter. After preoxygenation of both lungs for 30 min, the test lung was rendered hypoxic for 60 min by ventilation with 5% O2 in N2, with the control lung still being ventilated with 100% O2. Cardiac output was determined by thermodilution, and the distribution of blood flow between the lungs was assessed from the excretion of a continuously infused poorly soluble gas (SF6). The fractional perfusion of the test lung decreased from 53% to 25% of cardiac output within the first 15 min of unilateral hypoxia. The pulmonary artery mean pressure increased by 14% and the pulmonary vascular resistance (PVR) of the test lung increased by 54%. Venous admixture increased from 21% to 39% of cardiac output, while the "true" shunt was maintained at about 15%. Arterial oxygen tension (Pao2) fell from 45 kPa to 12 kPa. Prolonging the unilateral hypoxic challenge caused no further change in the redistribution of the pulmonary blood flow, but cardiac output and pulmonary artery mean pressure continued to increase to 40%-50% above control values after 1 h of hypoxia. The PVR of the test lung remained unchanged. The findings suggest that there is an immediate vasoconstrictor response to hypoxia in the human lung and that there is no further potentiation or diminution, of the response during a 60-min period of hypoxia.