Transmission of airway pressure to pleural space during lung edema and chest wall restriction

To investigate the influence of positive end-expiratory pressure (PEEP) on hemodynamic measurements we examined the transmission of airway pressure to the pleural space during varying conditions of lung and chest wall compliance. Eight ventilated anesthetized dogs were studied in the supine position with the chest closed. Increases in pleural pressure were similar for both small and large PEEP increments (5-20 cmH2O), whether measured in the esophagus (Pes) or in the juxtacardiac space by a wafer sensor (Pj). Increments in Pj exceeded the increments in Pes at all levels of PEEP and under each condition of altered lung and chest wall compliance. When chest wall compliance was reduced by thoracic and abdominal binding, the fraction of PEEP sensed in the pleural space increased as theoretically predicted. Acute edematous lung injury produced by oleic acid (OA) did not alter the deflation limb pressure-volume characteristics of the lung, provided that end-inspiratory volume was adequate. With the chest and abdomen restricted OA was associated with less than normal transmission of airway pressure to the pleural space, most likely because the end-inspiratory volume required to restore normal deflation characteristics was not attained. Together these results indicate that the influence of acute edematous lung injury on the transmission of airway pressure to the pleural space depends importantly on the peak volume achieved during inspiration.     

Locally measured shear moduli of pulmonary tissue and global lung mechanics in mechanically ventilated rats

This study was aimed at measuring shear moduli in vivo in mechanically ventilated rats and comparing them to global lung mechanics. Wistar rats (n = 28) were anesthetized, tracheally intubated, and mechanically ventilated in supine position. The animals were randomly assigned to the healthy control or the lung injury group where lung injury was induced by bronchoalveolar lavage. The respiratory system elastance E(rs) was analyzed based on the single compartment resistance/elastance lung model using multiple linear regression analysis. The shear modulus (G) of alveolar parenchyma was studied using a newly developed endoscopic system with adjustable pressure at the tip that was designed to induce local mechanostimulation. The data analysis was then carried out with an inverse finite element method. G was determined at continuous positive airway pressure (CPAP) levels of 15, 17, 20, and 30 mbar. The resulting shear moduli of lungs in healthy animals increased from 3.3 ± 1.4 kPa at 15 mbar CPAP to 5.8 ± 2.4 kPa at 30 mbar CPAP (P = 0.012), whereas G was ~2.5 kPa at all CPAP levels for the lung-injured animals. Regression analysis showed a negative correlation between G and relative E(rs) in the control group (r = -0.73, P = 0.008 at CPAP = 20 mbar) and no significant correlation in the lung injury group. These results suggest that the locally measured G were inversely associated with the elastance of the respiratory system. Rejecting the study hypothesis the researchers concluded that low global respiratory system elastance is related to high local resistance against tissue deformation.     

褪黑素对内毒素致大鼠急性肺损伤的保护作用

目的:研究内毒素(LPS)致大鼠急性肺损伤(ALI)时,p-p38蛋白激酶(p-p38MAPK)在肺组织的表达及褪黑素(MT)对肺组织的保护作用及其机制。方法:将72只健康雄性SD大鼠随机分为3组,每组24只,对照组(Control)、模型组(LPS)和褪黑素干预组(LPS+MT),采用气管内滴注LPS的方法建立大鼠ALI的模型,通过免疫组织化学染色和Western blot技术检测大鼠肺组织中p-p38蛋白激酶的表达变化,并在光镜下观察大鼠肺组织形态学变化。结果:Control组气道和肺组织可见反应极弱的p-p38蛋白激酶阳性细胞,散在分布于气道上皮细胞和肺泡上皮细胞;LPS组p-p38蛋白激酶阳性细胞较对照组明显增多(P0.05或P0.01),主要分布于浸润的炎症细胞、气道上皮细胞、肺泡上皮细胞和血管内皮细胞;LPS+MT组气道和肺组织中阳性细胞数较LPS组明显减少(P0.05或P0.01),Western blot结果与免疫组织化学一致。结论:LPS致大鼠急性肺损伤模型中,肺内炎性、非炎性细胞均有p38MAPK信号通路的激活;MT对急性肺损伤的保护机制可能与其抑制p38 MAPK信号通路的过度激活有关。     

High tidal volume ventilation induces lung injury after hepatic ischemia-reperfusion

Ischemia-reperfusion not only damages the affected organ but also leads to remote organ injuries. Hepatic inflow interruption usually occurs during hepatic surgery. To investigate the influence of liver ischemia-reperfusion on lung injury and to determine the contribution of tidal volume settings on liver ischemia-reperfusion-induced lung injury, we studied anesthetized and mechanically ventilated rats in which the hepatic inflow was transiently interrupted twice for 15 min. Two tidal volumes, 6 ml/kg as a low tidal volume (IR-LT) and 24 ml/kg as a high tidal volume (IR-HT), were assessed after liver ischemia-reperfusion, as well as after a sham operation, 6 ml/kg (NC-LT) and 24 ml/kg (NC-HT). Both the IR-HT and IR-LT groups had a gradual decline in the systemic blood pressure and a significant increase in plasma TNF-alpha concentrations. Of the four groups, only the IR-HT group developed lung injury, as assessed by an increase in the lung wet-to-dry weight ratio, the presence of significant histopathological changes, such as perivascular edema and intravascular leukocyte aggregation, and an increase in the bronchoalveolar lavage fluid TNF-alpha concentration. Furthermore, only in the IR-HT group was airway pressure increased significantly during the 6-h reperfusion period. These findings suggest that liver ischemia-reperfusion caused systemic inflammation and that lung injury is triggered when high tidal volume ventilation follows liver ischemia-reperfusion.     

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positive end-expiratory pressure and surfactant decrease lung injury during initiation of ventilation in fetal sheep

The initiation of ventilation in preterm, surfactant-deficient sheep without positive end-expiratory pressure (PEEP) causes airway injury and lung inflammation. We hypothesized that PEEP and surfactant treatment would decrease the lung injury from initiation of ventilation with high tidal volumes. Fetal sheep at 128-day gestational age were randomized to ventilation with: 1) no PEEP, no surfactant; 2) 8-cmH(2)O PEEP, no surfactant; 3) no PEEP + surfactant; 4) 8-cmH(2)O PEEP + surfactant; or 5) control (2-cmH(2)O continuous positive airway pressure) (n = 6-7/group). After maternal anesthesia and hysterotomy, the head and chest were exteriorized, and the fetus was intubated. While maintaining placental circulation, the fetus was ventilated for 15 min with a tidal volume escalating to 15 ml/kg using heated, humidified, 100% nitrogen. The fetus then was returned to the uterus, and tissue was collected after 30 min for evaluation of early markers of lung injury. Lambs receiving both surfactant and PEEP had increased dynamic compliance, increased static lung volumes, and decreased total protein and heat shock proteins 70 and 60 in bronchoalveolar lavage fluid compared with other groups. Ventilation, independent of PEEP or surfactant, increased mRNA expression of acute phase response genes and proinflammatory cytokine mRNA in the lung tissue compared with controls. PEEP decreased mRNA for cytokines (2-fold) compared with groups receiving no PEEP. Surfactant administration further decreased some cytokine mRNAs and changed the distribution of early growth response protein-1 expression. The use of PEEP during initiation of ventilation at birth decreased early mediators of lung injury. Surfactant administration changed the distribution of injury and had a moderate additive protective effect.     

Role of histamine in acute oleic acid-induced lung injury

The action of histamine in oleic acid (OA)-induced injury was investigated using the isolated guinea pig lung perfused with blood-free media. OA infusion caused a significant increase in pulmonary arterial pressure, airway inspiratory pressure, lung weight, and protein flux across the alveolar-capillary barrier. These changes were dose dependent and caused injury regardless of the chemical form of OA (salt or free acid). Triolein (a neutral fat) infused at comparable emulsion particle size did not alter lung weight or bronchoalveolar lavage protein concentration in the perfused lung, suggesting that mechanical obstruction or emboli per se is not responsible for initiating early events in OA-induced injury. Infusion of OA caused a significant early histamine release into the venous effluent in the presence of aminoguanidine, a histamine catabolism inhibitor. Pretreatment with H1-receptor antagonists significantly attenuated OA-induced increase in lung weight and protein leak. These data support the link between OA-induced mast cell degranulation, histamine release, and OA-induced edema.     

Influence of CPAP on reflex responses to tracheal irritation in anesthetized humans

We investigated the effects of lung inflation during continuous positive airway pressure breathing (CPAP) on airway defensive reflexes in 10 enflurane-anesthetized spontaneously breathing humans. The airway defensive reflexes were induced by instillation into the trachea of 0.5 ml of distilled water at two different levels of end-expiratory pressure (0 and 10 cmH2O CPAP). The tracheal irritation at an end-expiratory pressure of 0 cmH2O caused a variety of reflex responses including apnea, spasmodic panting, expiration reflex, cough reflex, an increase in heart rate, and an increase in blood pressure. Lung inflation during CPAP of 10 cmH2O did not exert any influence on these reflex responses in terms of the types, latencies, and durations of reflex responses although the intensity of the expiration reflex and cough reflex was augmented by lung inflation. Our results suggest that the pulmonary stretch receptors do not play an important role in the mechanisms of airway defensive reflexes in humans.     

Changes in proteoglycans and lung tissue mechanics during excessive mechanical ventilation in rats

Excessive mechanical ventilation results in changes in lung tissue mechanics. We hypothesized that changes in tissue properties might be related to changes in the extracellular matrix component proteoglycans (PGs). The effect of different ventilation regimens on lung tissue mechanics and PGs was examined in an in vivo rat model. Animals were anesthetized, tracheostomized, and ventilated at a tidal volume of 8 (VT(8)), 20, or 30 (VT(30)) ml/kg, positive end-expiratory pressure of 0 (PEEP(0)) or 1.5 (PEEP(1.5)) cmH(2)O, and frequency of 1.5 Hz for 2 h. The constant-phase model was used to derive airway resistance, tissue elastance, and tissue damping. After physiological measurements, one lung was frozen for immunohistochemistry and the other was reserved for PG extraction and Western blotting. After 2 h of mechanical ventilation, tissue elastance and damping were significantly increased in rats ventilated at VT(30)PEEP(0) compared with control rats (ventilated at VT(8)PEEP(1.5)). Versican, basement membrane heparan sulfate PG, and biglycan were all increased in rat lungs ventilated at VT(30)PEEP(0) compared with control rats. At VT(30)PEEP(0), heparan sulfate PG and versican staining became prominent in the alveolar wall and airspace; biglycan was mostly localized in the airway wall. These data demonstrate that alterations in lung tissue mechanics with excessive mechanical ventilation are accompanied by changes in all classes of extracellular matrix PG.     

Effect of PEEP on respiratory mechanics in anesthetized paralyzed humans.

With the use of the technique of rapid airway occlusion during constant flow inflation, respiratory mechanics were studied in eight anesthetized paralyzed supine normal humans during zero (ZEEP) and positive end-expiratory pressure (PEEP) ventilation. PEEP increased the end-expiratory lung volume by 0.49 liter. The changes in transpulmonary and esophageal pressure after flow interruption were analyzed in terms of a seven-parameter "viscoelastic" model. This allowed assessment of static lung and chest wall elastance (Est,L and Est,W), partitioning of overall resistance into airway interrupter (Rint,L) and tissue resistances (delta RL and delta RW), and computation of lung and chest wall "viscoelastic constants." With increasing flow, Rint,L increased, whereas delta RL and delta RW decreased, as predicted by the model. Est,L, Est,W, and Rint,L decreased significantly with PEEP because of increased lung volume, whereas delta R and viscoelastic constants of lung and chest wall were independent of PEEP. The results indicate that PEEP caused a significant decrease in Rint,L, Est,L, and Est,W, whereas the dynamic tissue behavior, as reflected by delta RL and delta RW, did not change.     

Effect of raised thoracic pressure and volume on 99mTc-DTPA clearance in humans

Although positive airway pressure is often used to treat acute pulmonary edema, the effects on epithelial solute flux are not well known. We measured independently the effect of 1) positive pressure and 2) voluntary hyperinflation on the clearance of inhaled technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) in six nonsmokers and six smokers. Lung volumes were monitored by inductance plethysmography. Each subject was studied in four situations: 1) low end-expiratory volume (LO-), 2) low volume plus 9 cmH2O continuous positive airway pressure (LO+), 3) high end-expiratory volume (HI-), and 4) high volume plus continuous positive airway pressure (HI+). The clearance half time of 99mTc-DTPA for the nonsmokers decreased from 64.8 +/- 7.0 min (mean +/- SE) at LO- to 23.2 +/- 5.3 min at HI- (P less than 0.05). Positive pressure had no synergistic effect. The mean clearance half time for the smokers was faster than nonsmokers at base line but unaffected by similar changes in thoracic volume and pressure. We conclude that, in nonsmokers, positive airway pressure increases 99mTc-DTPA clearance primarily through an increase in lung volume and that smokers are immune to these effects.     

Effects of various antioxidants on endotoxin-induced lung injury and gene expression: mRNA expressions of MnSOD, interleukin-1beta and iNOS

Antioxidants have been shown to be effective in attenuating acute lung injury. In this study, we determine the effects of various antioxidants by different mechanisms on the lipopolysaccharide (LPS)-induced changes. LPS was administered intravenously at a dose of 10 mg/kg to anesthetized rats. LPS induced a significant decrease in blood pressure (P < 0.01) and increased exhaled nitric oxide (NO) from 3.60+/-0.18 to 35.53+/-3.23 ppb (P < 0.01) during an observation period of 4 h. Plasma nitrate concentrations also increased from 0.61+/-0.06 to 1.54+/-0.22 micromol/l (P < 0.05). LPS-induced oxygen radical release from white blood cells isolated from rat peripheral blood also increased significantly (P < 0.001). After the experiment, the lung weight was obtained and lung tissues were taken for the determination of mRNA expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and manganese superoxide dismutase (MnSOD). Histological examination of the lungs was also performed. In the control group injected with saline solution, mRNA expressions of iNOS, IL-1beta, TNF-alpha and MnSOD were absent. Four hours after LPS administration, mRNA expressions of iNOS, IL-1beta, and MnSOD were significantly enhanced, but TNF-alpha was not discernibly expressed. LPS also caused a twofold increase in lung weight. Pathological examination revealed endothelial cell damage and interstitial edema. Various antioxidants were given 1 h after LPS administration. These agents include SOD, catalase (CAT), SOD + CAT or vitamin C (ascorbic acid). These antioxidants effectively reversed the systemic hypotension, reduced the quantity of exhaled NO and plasma nitrate concentration, and prevented acute lung injury. Administration of various antioxidants also significantly attenuated LPS-induced oxygen radical release by rat white blood cells. LPS induced mRNA expressions of MnSOD and iNOS were significantly depressed by these antioxidants. However, only SOD + CAT and vitamin C inhibited the mRNA expression of IL-1beta. These results suggest that oxygen radicals are responsible for LPS-induced lung injury. Antioxidants can attenuate the lung injury by inhibiting mRNA expressions of iNOS and IL-1beta.     

Airway response to deep inspiration: role of inflation pressure.

Deep inspirations (DIs) have been shown to have both bronchoprotective and bronchodilator effects in healthy subjects; however, the bronchodilator effects of a DI appear to be impaired in asthmatic compared with healthy subjects. Because the ability to generate high transpulmonary pressures at total lung capacity depends on both the lung properties and voluntary effort, we wondered how the response of airways to DI might be altered if the maneuver were done with less than maximal inflation. The present work was undertaken to examine the effects of varying the magnitude of lung inflation during the DI maneuver on subsequent airway caliber. In five anesthetized and ventilated dogs during methacholine infusion, changes in airway size after DIs of increasing magnitude were measured over the subsequent 5-min period using high-resolution computed tomography. Results show that the magnitude of lung inflation is extremely important, leading to a qualitative change in the airway response. A large DI (45 cmH(2)O airway pressure) caused subsequent airway dilation, whereas smaller DIs (< or =35 cmH(2)O) caused bronchoconstriction. The precise mechanism underlying these observations is uncertain, but it seems to be related to an interaction between intrinsic properties of the contracted airway smooth muscle and the response to mild stretch.     

Effects of OKY 1581 on bronchoconstrictor responses to arachidonic acid and PGH2

The influence of OKY 1581, a thromboxane synthase inhibitor, on airway responses to arachidonic acid and endoperoxide, [prostaglandin (PG) H2], were investigated in anesthetized, paralyzed, mechanically ventilated cats. Intravenous injections of arachidonic acid and PGH2 caused dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic and static compliance. OKY 1581 significantly decreased airway responses to arachidonic acid but not to PGH2. Sodium meclofenamate, a cyclooxygenase inhibitor, abolished airway responses to arachidonic acid but had no effect on airway responses to PGH2. OKY 1581 or meclofenamate has no effect on airway responses to PGF2 alpha, PGD2, or U 46619, a thromboxane mimic. In microsomal fractions from the lung, OKY 1581 inhibited thromboxane formation without decreasing prostacyclin synthesis or cyclooxygenase activity. These studies show that OKY 1581 is a selective thromboxane synthesis inhibitor in the cat lung and suggest that a substantial part of the bronchoconstrictor response to arachidonic acid is due to thromboxane A2 formation. Moreover, the present data suggest that airway responses to endogenously released and exogenous PGH2 are mediated differently and that a significant part of the response to exogenous PGH2 may be due to activation of an endoperoxide/thromboxane receptor, since responses to PGH2 are blocked by the thromboxane receptor antagonist SQ 29548.     

Release of atriopeptin in the rat by vasoconstrictors or water immersion correlates with changes in right atrial pressure

Vasopressin, its 1-deamino analog (dAVP), angiotensin II, and phenylephrine, administered intravenously, increased plasma atriopeptin immunoreactivity in chloral hydrate-anesthetized rats. A continuous one hour infusion of either dAVP or phenylephrine caused a sustained elevation in: a) systemic blood pressure; b) right atrial pressure; c) left ventricular end diastolic pressure; and d) plasma atriopeptin immunoreactivity. While continuous infusion of angiotensin II also produced a sustained elevation in left ventricular end diastolic pressure, the changes in right atrial pressure and plasma atriopeptin were only transient. These data suggest that plasma atriopeptin most closely correlates with right atrial pressure. Consistent with this hypothesis, we found that the release of atriopeptin directly correlated with changes in right atrial pressure in anesthetized, water-immersed rats.     

The effect of body temperature on the dynamic respiratory system compliance–breathing frequency relationship in the rat

The mechanical inhomogeneity of the respiratory system is frequently investigated by measuring the frequency dependence of dynamic compliance, but no data are currently available describing the effects of body temperature variations. The aim of the present report was to study those effects in vivo. Peak airway pressure was measured during positive pressure ventilation in eight anesthetized rats while breathing frequency (but not tidal volume) was altered. Dynamic compliance was calculated as the tidal volume/peak airway pressure, and measurements were taken in basal conditions (mean rectal temperature 37.3 °C) as well as after total body warming (mean rectal temperature 39.7 °C). Due to parenchymal mechanical inhomogeneity and stress relaxation-linked effects, the normal rat respiratory system exhibited frequency dependence of dynamic lung compliance. Even moderate body temperature increments significantly reduced the decrements in dynamic compliance linked to breathing rate increments. The results were analyzed using Student’s and Wilcoxon’s tests, which yielded the same results (p < 0.05). Body temperature variations are known to influence respiratory mechanics. The frequency dependence of dynamic compliance was found, in the experiments described, to be temperature-dependent as temperature variations affected parenchymal mechanical inhomogeneity and stress relaxation. These results suggest that body temperature variations should be taken into consideration when the dynamic compliance–breathing frequency relationship is being examined during clinical assessment of inhomogeneity of lung parenchyma in patients.     

Influence of tongue muscle contraction and transmural pressure on nasopharyngeal geometry in the rat

The mammalian pharynx is a hollow muscular tube that participates in ingestion and respiration, and its size, shape, and stiffness can be altered by contraction of skeletal muscles that lie inside or outside of its walls. MRI was used to determine the interaction between pharyngeal pressure and selective stimulation of extrinsic tongue muscles on the shape of the rat nasopharynx. Pressure (-9, -6, -3, 3, 6, and 9 cmH?O) was applied randomly to the isolated pharyngeal airway of anesthetized rats that were positioned in a 4.7-T MRI scanner. The anterior-posterior (AP) and lateral diameters of the nasopharynx were measured in eight axial slices at each level of pressure, with and without bilateral hypoglossal nerve stimulation (0.1-ms pulse, 1/3 maximal force, 80 Hz). The rat nasopharynx is nearly circular, and positive pharyngeal pressure caused similar expansion of AP and lateral diameters; as a result, airway shape (ratio of lateral to AP diameter) remained constant. Negative pressure did not change AP or lateral diameter significantly, suggesting that a negative pressure reflex activated the tongue or other pharyngeal muscles. Stimulation of tongue protrudor muscles alone or coactivation of protrudor and retractor muscles caused greater AP than lateral expansion, making the nasopharynx slightly more elliptical, with the long axis in the AP direction. These effects tended to be more pronounced at negative pharyngeal pressures and greater in the caudal than rostral nasopharynx. These data show that stimulation of rodent tongue muscles can adjust pharyngeal shape, extending previous work showing that tongue muscle contraction alters pharyngeal compliance and volume, and provide physiological insight that can be applied to the treatment of obstructive sleep apnea.     

Mechanisms of early pulmonary neutrophil sequestration in ventilator-induced lung injury in mice

Polymorphonuclear leukocytes (PMN) play an important role in ventilator-induced lung injury (VILI), but the mechanisms of pulmonary PMN recruitment, particularly early intravascular PMN sequestration during VILI, have not been elucidated. We investigated the physiological and molecular mechanisms of pulmonary PMN sequestration in an in vivo mouse model of VILI. Anesthetized C57/BL6 mice were ventilated for 1 h with high tidal volume (injurious ventilation), low tidal volume and high positive end-expiratory pressure (protective ventilation), or normal tidal volume (control ventilation). Pulmonary PMN sequestration analyzed by flow cytometry of lung cell suspensions was substantially enhanced in injurious ventilation compared with protective and control ventilation, preceding development of physiological signs of lung injury. Anesthetized, spontaneously breathing mice with continuous positive airway pressure demonstrated that raised alveolar pressure alone does not induce PMN entrapment. In vitro leukocyte deformability assay indicated stiffening of circulating leukocytes in injurious ventilation compared with control ventilation. PMN sequestration in injurious ventilation was markedly inhibited by administration of anti-L-selectin antibody, but not by anti-CD18 antibody. These results suggest that mechanical ventilatory stress initiates pulmonary PMN sequestration early in the course of VILI, and this phenomenon is associated with stretch-induced inflammatory events leading to PMN stiffening and mediated by L-selectin-dependent but CD18-independent mechanisms.     

过氧亚硝基阴离子介导内毒素致肺血管损伤及胆囊收缩素的保护作用

本文探讨过氧亚硝基阴离子（ONOO^-）在内毒素致肺血管损伤中的介导作用和八肽胆囊收缩素（CCK）的保护作用及其机制。结果发现,内毒素主要成分脂多糖（LPS）可诱导大鼠肺组织生成ONOO^-1,ONOO^-能导致肺微血管壁通透性明显增加和肺脏严重病理变化;ONOO^-可引起离体肺动脉反应性异常改变,LPS也可产生类似变化;ONOO^-有较弱的舒血管作用并受到内皮细胞的抑制性调节;LPS诱导培养的牛肺动脉内皮细胞（BPAEC）产生增多的ONOO^-参与介导内皮细胞本身的损伤;CCK能拮抗LPS对BPAEC的损伤效应,此作用由CCK受体介导,并与抑制ONOO^-生成有关。结果提示,清除ONOO^-或减少ONOO^-生成可为防治内毒素引起的急性肺损伤等病理过程提供新对策;CCK是一种有应用前景的细胞保护因子。