Serial assessment of pulmonary microvascular permeability in a patient developing the adult respiratory distress syndrome.

Serial measurements of lung extravascular accumulation of 113mIndium-transferrin were made in a patient with acute respiratory failure during the development of the adult respiratory distress syndrome (ARDS). Abnormality of this index of pulmonary microvascular permeability antedated radiological change and appeared to predict the onset of frank ARDS.     

基质金属蛋白酶9与急性肺损伤/急性呼吸窘迫综合征

急性呼吸窘迫综合征的本质是弥漫性肺泡毛细血管膜损伤、血管通透性增加所致的通透性肺水肿.基质金属蛋白酶可以降解细胞外基质蛋白,使肺毛细血管通透性增加,引发肺水肿,导致急性肺损伤和(或)急性呼吸窘迫综合征.本文就基质金属蛋白酶9在急性肺损伤/急性呼吸窘迫综合征中的作用及研究进展进行综述.     

Ultrastructural abnormalities in increased-permeability pulmonary edema

A general clinical impression is that increased microvascular permeability following acute lung injury always leads to pulmonary edema. The ARDS is a final pathway of acute lung injury. A number of agents may initiate acute lung injury, either directly or indirectly, via cellular and humoral mediators. Clinical and experimental animal studies indicate that both the microvascular and alveolar-airway barriers are susceptible to injury. Unfortunately, the spectrum of cellular damage is nonspecific and quite uniform, regardless of the injurious agent. Thus pathologic examination often reveals little about the exact underlying etiology of the lung injury. This situation has minimized the diagnostic value of lung biopsies in clinical cases of increased-permeability pulmonary edema. Nonetheless, the pathologic information has been, and will continue to be, invaluable to understanding the structural and functional relationships present in experimental models of increased-permeability pulmonary edema.     

Treatment with neutralising antibody against cytokine induced neutrophil chemoattractant (CINC) protects rats against acute pancreatitis associated lung injury

BACKGROUND: Lung injury manifest clinically as adult respiratory distress syndrome (ARDS) is a common cause of morbidity and mortality following acute pancreatitis (AP). Neutrophils play a critical role in the progression of AP to ARDS. C-x-C chemokines are potent neutrophil chemoattractants and activators and have been implicated in AP. AIMS: To evaluate the effect of blocking the C-x-C chemokine, cytokine induced neutrophil chemoattractant (CINC), in AP on pancreatic inflammation and the associated lung injury in rats. METHODS: AP was induced by hourly intraperitoneal injections of caerulein. Goat anti-CINC antibody was administered either before or after starting caerulein injections to evaluate the prophylactic and therapeutic effects, respectively. Severity of AP was determined by measuring plasma amylase, pancreatic water content, and pancreatic myeloperoxidase (MPO) activity as a measure of neutrophil sequestration in the pancreas. Lung injury was determined by measurement of pulmonary microvascular permeability and lung MPO activity. RESULTS: Treatment with anti-CINC antibody had little effect on caerulein induced pancreatic damage. However, it reduced the caerulein mediated increase in lung MPO activity as well as lung microvascular permeability when administered either prophylactically (lung MPO (fold increase over control): 1.53 (0.21) v. 3.30 (0.46), p<0.05; microvascular permeability (L/P%): 0.42 (0.07) v. 0.77 (0.11), p<0.05) or therapeutically (lung MPO (fold increase over control): 2.13 (0.10) v 4.42 (0.65), p<0.05; microvascular permeability (L/P%): 0.31 (0.05) v 0.79 (0.13), p<0.05). CONCLUSION: Treatment with anti-CINC antibody afforded significant protection against pancreatitis associated lung injury. These results suggest that CINC plays an important role in the systemic inflammatory response in AP.     

Effective attenuation of endotoxin-induced acute lung injury by 2,3-diacetyloxybenzoic acid in two independent animal models

The pathology of acute lung injury (ALI) is often modeled in animal studies by the administration of lipopolysaccharide (LPS), which results in an endotoxemia with sequelae similar to that seen in acute respiratory distress syndrome (ARDS). Here we report the results of two studies designed to examine the efficacy of a novel agent, 2,3-diacetyloxybenzoic acid (2,3-DABA), in the treatment of LPS-induced ALI. In two separate animal models, 2,3-DABA was effective in significantly reducing lung microvascular permeability, a condition commonly seen in ARDS, which results in pulmonary edema and respiratory insufficiency. In each model, it is demonstrated that the mechanism by which 2,3-DABA exerts this effect occurs subsequent to the recruitment of neutrophils to the site of inflammation. Lung permeability was significantly decreased in both models by treatment with 2,3-DABA, suggesting that this agent, either alone or in combination therapy, may be useful in the treatment of ALI associated with ARDS.     

Occurrence of the adult respiratory distress syndrome in neutropenic patients

Neutrophils are believed to play an essential role in the pathogenesis of the adult respiratory distress syndrome (ARDS). This concept is largely based on the observation that neutrophil depletion protects against altered pulmonary vascular permeability in several models of acute lung injury produced in laboratory animals. Four patients who developed ARDS during periods of profound neutropenia are presented. These patients met commonly accepted clinical and roentgenographic criteria for the syndrome, and each had the characteristic findings of diffuse alveolar damage by lung histologic examination. The failure of this degree of neutropenia to protect against ARDS in humans raises questions about whether neutrophils or neutrophil products are essential in the pathogenesis of the syndrome.     

Assessment of lung injury in the adult respiratory distress syndrome using multiple indicator dilution curves

To assess its usefulness as an index of lung injury in critically ill patients with respiratory failure, the lung microvascular permeability surface area product for urea (14C-PSu) was measured using a multiple radioisotopic indicator dilution technique in 10 patients with the adult respiratory distress syndrome (ARDS) and in a control population of 5 patients without ARDS. The mean values for 14C-PSu and for extravascular lung water (EVLW) were both significantly elevated in patients with ARDS compared with those in control patients (14C-PSu: 18.7 +/- 4.4 versus 7.6 +/- 0.7, p less than 0.05; EVLW: 676 +/- 55 versus 269 +/- 53, p less than 0.001); 14C-PSu and EVLW were significantly correlated (R = 0.52, p less than 0.001). In the patients with ARDS, 14C-PSu and oxygenation, assessed as the alveolar-arterial oxygen difference, did not appear to be correlated. Repeated measurements of 14C-PSu were variable in the 3 control patients in whom 4 or more measurements were obtained (SD = 50, 57, and 54% of the mean values, respectively); 14C-PSu did not predict clinical outcome assessed by survival of individual patients with ARDS. These data suggest that measurement of 14C-PSu in critically ill patients is a clinically applicable parameter that reflects the degree of microvascular injury in groups of patients. However, our study did not indicate a clear advantage of 14C-PSu over EVLW in assessing lung injury in this patient population. The variability in 14C-PSu control patients also suggests that directional changes in 14C-PSu, as a measure of changes in the degree of lung microvascular dysfunction, should be interpreted with caution.     

Abnormal neutrophil-pulmonary interaction in the adult respiratory distress syndrome. Qualitative and quantitative assessment of pulmonary neutrophil kinetics in humans with in vivo 111indium neutrophil scintigraphy

In the absence of direct toxins, the majority of evidence from animal models suggests that neutrophils (PMN) are necessary for the full expression of the abnormal pulmonary permeability accompanying acute microvascular lung injury. We therefore studied the role of the PMN in the human correlate of this disease, the adult respiratory distress syndrome (ARDS), by assessing the pulmonary retention of infused autologous 111Indium-labeled PMN (PMN-In). We evaluated 79 patients, prospectively categorized as: "active" ARDS (Aa; n = 30), "active" ARDS and concurrent corticosteroid therapy (As; n = 11), "resolving" ARDS (Ar; n = 13), sepsis without pulmonary edema (S; n = 7), and cardiac pulmonary edema (C; n = 18). This clinical separation was confirmed by retrospective analysis of associated measures of hemodynamic and respiratory dysfunction. We found that both analog scintigrams (positive/negative for diffuse pulmonary PMN-In sequestration) and computer-assisted quantitative analysis in 46 patients (T 1/2 of first hour demargination and percentage of peak activity/pixel/second remaining at 17 to 20 h) showed a significant rank order decrease in the pulmonary retention of labeled PMN-In through the Groups Aa----As----S----Ar----C. Our findings recognized aspects of in vivo PMN-In behavior that implied pathophysiologic differences between groups of critically ill patients in either the PMN themselves or in PMN-pulmonary endothelial interaction. This demonstrates the possibility of abnormal in vivo PMN-endothelial interaction in ARDS by virtue of the greater pulmonary localization of PMN in active ARDS versus resolving disease, septic non-ARDS states, and cardiac pulmonary edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

乙酰化白藜芦醇对脂多糖诱导急性肺损伤中微循环修复作用机制探究

目的观察脂多糖(LPS)诱导急性肺损伤大鼠肺组织中微循环的变化,探讨乙酰化白藜芦醇对其干预作用及机制。方法 32只SD大鼠随机分为空白对照组、LPS处理组、乙酰化白藜芦醇预处理组和白藜芦醇预处理组,每组8只。采用气管内滴注LPS(5 mg/kg)的方法制作急性肺损伤动物模型,观察病理变化、肺组织湿/干重比值,用伊文思蓝法检测肺微血管通透性,用酶联免疫吸附试验法检测肺组织中肿瘤坏死因子α和白细胞介素1β的含量,用蛋白质印迹法检测细胞骨架重构相关蛋白FAK、cofilin的表达变化,免疫荧光观察肺微血管内皮细胞单层细胞间隙改变情况。结果 LPS干预4 h后,大鼠肺部损伤明显,肿瘤坏死因子α和白细胞介素1β的含量增高,肺湿/干重比值及通透性明显增加,FAK-cofilin通路明显激活,肺微血管内皮单层细胞间隙明显增加;乙酰化白藜芦醇预处理显著减轻了LPS导致的急性肺损伤,减少了炎症因子的释放,并且抑制了FAK-cofilin通路的激活及肺微血管内皮单层细胞间隙的增加。结论肺微循环的改变参与了LPS诱导肺损伤的发生发展,乙酰化白藜芦醇能够通过抑制FAK-cofilin通路减轻肺损伤。     

Re-expansion, re-oxygenation, and rethinking

In a 1902 American Journal of the Medical Sciences case report, Riesman described "albuminous expectoration" following thoracentesis, a phenomenon that is now recognized as re-expansion pulmonary edema (RPE). Both cellular and biochemical mechanisms that produce lung injury in RPE have been described recently. Pathophysiologically, this unilateral edematous lung injury resembles the adult respiratory distress syndrome (ARDS) because both are characterized by intra-alveolar-activated neutrophils and markedly increased lung capillary permeability. Biochemical mechanisms that operate in RPE are analogous to those in diverse re-oxygenation (reperfusion) injuries that have been described recently in the heart, kidney, brain, and intestine. Re-oxygenated lung tissue appears to produce excess superoxide and other cytotoxic oxygen metabolites, although lung xanthine oxidase, the commonly recognized source of these oxidants, is exceedingly low. Riesman's critical analyses of the re-expansion edema fluid in his case provided an impetus for others to hypothesize that increased permeability pulmonary edema in RPE represented re-oxygenation injury of the lung microvasculature.     

Changes and significance of chemiluminescence of polymorphonuclear leukocytes in endotoxin-induced lung injury in conscious sheep]

The chemiluminescence (CL) of polymorphonuclear leukocytes and its relation with pulmonary microvascular permeability after endotoxin-induced lung injury in conscious sheep with lung lymph fistula were observed. Four hours after the injury the CL of PMNs increased from 0.27 cpm/PMN of baseline to 0.69 cpm/PMN (P < 0.05). The increment of the CL had positive correlation with the increment of lung lymph flow or permeability index (r = 0.632 0.638 P < 0.05), suggesting that the increase of pulmonary microvascular permeability after the endotoxin injury had relation with the increase of the respiratory tract of PMNs.     

Lung injury in acute experimental pancreatitis in rats I. Morphological Studies

The pathogenesis of pancreatitis-related pulmonary injury was studied at the light- and electronmicroscopic level. Experimental pancreatitis was induced in rats by infusion of supramaximal doses of cerulein for 12 h. Investigations were carried out 3, 6, and 12 h after the start of infusion and 12, 48, and 72 h after the end of pancreatitis induction. Initial manifestations of pancreatitis-associated lung injury revealed a pronounced clustering of polymorphonuclear leukocytes in pulmonary microvessels, followed by severe damage of alveolar endothelial cells. Consecutively, the increase in vascular permeability of the lung resulted in interstitial edema formation. Structural changes were maximal after 12 h and reversed completely after 84 h. In conclusion, the structural appearance of pulmonary injury in cerulein-induced pancreatitis was similar to that reported in early stages of the adult respiratory distress syndrome (ARDS). It is suggested that polymorphonuclear granulocytes play a crucial role in the pathogenesis of pancreatitis-related lung injury.     

Lung injury in acute experimental pancreatitis in rats. I. Morphological studies.

The pathogenesis of pancreatitis-related pulmonary injury was studied at the light- and electronmicroscopic level. Experimental pancreatitis was induced in rats by infusion of supramaximal doses of cerulein for 12 h. Investigations were carried out 3, 6, and 12 h after the start of infusion and 12, 48, and 72 h after the end of pancreatitis induction. Initial manifestations of pancreatitis-associated lung injury revealed a pronounced clustering of polymorphonuclear leukocytes in pulmonary microvessels, followed by severe damage of alveolar endothelial cells. Consecutively, the increase in vascular permeability of the lung resulted in interstitial edema formation. Structural changes were maximal after 12 h and reversed completely after 84 h. In conclusion, the structural appearance of pulmonary injury in cerulein-induced pancreatitis was similar to that reported in early stages of the adult respiratory distress syndrome (ARDS). It is suggested that polymorphonuclear granulocytes play a crucial role in the pathogenesis of pancreatitis-related lung injury.     

Existence of leukotoxin 9,10-epoxy-12-octadecenoate in lung lavages from rats breathing pure oxygen and from patients with the adult respiratory distress syndrome

Pulmonary influxed neutrophils have been suggested to be involved in the development of hyperoxia-induced lung injury. We recently revealed that a highly toxic substance, 9,10-epoxy-12-octadecenoate, is biosynthesized by human neutrophils, thus it was named leukotoxin. Because hyperoxia-induced lung injury is a model of adult respiratory distress syndrome (ARDS), this study was designed to investigate whether or not leukotoxin is involved in the genesis of pulmonary oxygen toxicity and ARDS. After exposure to hyperoxia for 60 h, rats showed acute pulmonary edema, which was evidenced by increased lung weight, albumin concentrations, and angiotensin-converting enzyme (ACE) activities in lung lavages. These changes were correlated with an increased number of neutrophils. We detected leukotoxin in lung lavages of rats after exposure to hyperoxia for 60 h by high performance liquid chromatography and gas-chromatography/mass spectrometry. After intravenous injection of leukotoxin (100 mumol/kg) to rats, acute edematous lung injury occurred showing increases in lung weight, lung lavage albumin concentrations, and lung lavage ACE activities. In the lung lavages obtained from 5 patients with ARDS, significant increases in albumin concentrations and ACE activities were observed compared with those from subjects without pulmonary disease. Moreover, considerable amounts of leukotoxin, 38.5 +/- 21.9 nmol/lung lavage, were observed in the lavages from patients with ARDS. These findings suggest that leukotoxin plays an important role in the genesis of acute edematous lung damage in pulmonary oxygen toxicity, and that leukotoxin also links with the development of lung injury observed in patients with ARDS.     

Increased intestinal protein permeability in a model of lung injury induced by phorbol myristate acetate

Multiple nonpulmonary organ failure is a frequent complication of the adult respiratory distress syndrome (ARDS), and contributes significantly to the high mortality rate associated with this disorder. Although previous studies suggest that systemic organ injury may be an integral component of ARDS, little is known about the specific functional alterations that occur in these target organs. The present study was designed, therefore, to test the hypothesis that endothelial damage, as assessed by microvascular permeability changes, develops in systemic organs in a model of acute lung injury. To test this postulate, the microvascular permeability for total protein was estimated using the steady-state relationship between the lymph (CL) to plasma (Cp) protein concentration ratio (i.e., CL/Cp) and lymph flow in autoperfused cat ileum preparations. Specifically, CL/Cp was measured in five cats, 2 h after acute lung injury was induced by intravenously administered phorbol myristate acetate (PMA), 15 micrograms/kg, and the results were compared with those of seven time-matched control animals. Prior to PMA infusion, the PaO2/FIO2 ratio was 451 +/- 28 in both groups and remained unchanged (486 +/- 26) in the control group. By contrast, the PaO2/FIO2 ratio fell to 275 +/- 95 after PMA infusion (p less than 0.05). In addition, whereas CL/Cp was 0.099 +/- 0.008 in the control animals, it increased to 0.36 +/- 0.06 in the PMA-injured animals (p less than 0.01). In summary, this study demonstrated that in this model of acute lung injury produced by PMA-induced activation of circulating inflammatory cells, both acute lung injury and systemic organ injury (i.e., morphologic and permeability alterations) occurred.     

Lung microvascular transport properties measured by multiple indicator dilution methods in patients with adult respiratory distress syndrome. A comparison between patients reversing respiratory failure and those failing to reverse

We conducted indicator dilution studies on the lungs of patients in the early phases of adult respiratory distress syndrome (ARDS) to test the hypothesis that capillary permeability was increased in patients with respiratory failure. Indicator dilution studies were performed using 51Cr-erythrocytes, 125I-albumin, 14C-urea, and 3H-water as tracers. The injectate was infused as a bolus into a central venous line. Peripheral arterial blood was collected and counted for radioactivity. Mathematical analysis of the indicator curves yielded cardiac output, measures of the product of capillary permeability and surface area for urea (PS and D1/2S), the intravascular lung volume (Vv), and the extravascular lung water volume (Ve). Permeability was separated from surface area by normalizing PS and D1/2S to Vv. Patients could be divided into 16 in whom blood gas determinations and radiologic criteria for ARDS were reversed and 23 in whom they were not. We examined indicator dilution and other measures of lung function in the two groups to determine whether significant differences in microvascular function existed. PS and PS/Vv were significantly higher in the nonreversal patients. Ve was above normal, but not different between groups. Linear regression analysis showed significant correlations for all of the following in the nonreversal group: Ve and all measures of permeability, pulmonary vascular resistance (PVR), and the inverse of permeability-surface area measures and AaDO2 and PVR. Only measures of Ve and PS correlated in the reversal group. These results support the hypothesis that capillary permeability is increased in patients with early ARDS and continuing respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

清除循环肿瘤坏死因子对急性肺损伤的影响

目的研究亲和免疫吸附清除循环肿瘤坏死因子（ＴＮＦ）对内毒素性急性肺损伤动物的保护作用。方法以６１只新西兰白兔为实验动物，建立内毒素性急性肺损伤模型。随机分为三组：（１）免疫吸附组（２７只），颈静脉注射自制脂多糖（ＬＰＳ）１００×１０８ｃｆｕ·ｋｇ－１后１小时开始血液灌流，通过含重组肿瘤坏死因子α（ｒＨｕＴＮＦα）单克隆抗体的吸附柱，灌流时间２小时；（２）致伤组（２７只），颈静脉注射ＬＰＳ，无吸附柱，仅有相同血量的体外循环；（３）对照组（７只），颈静脉注射生理盐水２ｍｌ，无吸附柱，仅有体外循环。通过亲和免疫吸附清除循环ＴＮＦ，观察了肺系数、肺通透指数、肺泡灌洗液（ＢＡＬＦ）中ＴＮＦ和白细胞介素８（ＩＬ８）水平、白细胞数的变化以及对存活率的影响。结果免疫吸附组能有效清除循环ＴＮＦ、ＢＡＬＦ中ＴＮＦ及ＩＬ８水平较致伤组显著降低（Ｐ＜０．０１），肺毛细血管通透性等指标明显改善（Ｐ＜０．０１），存活率提高（Ｐ＜０．０１）。结论免疫吸附清除循环ＴＮＦ，能有效地保护内毒素所致的急性肺损伤。     

Adult Respiratory Distress Syndrome

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung.Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

Adult respiratory distress syndrome: do selective anticoagulants help?

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

Is There a Role for β-Adrenoceptor Agonists in the Management of Acute Lung Injury and the Acute Respiratory Distress Syndrome?

Despite improvements in general supportive care and ventilatory strategies designed to limit lung injury, no specific pharmacological therapy has yet proven to be efficacious in the management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Based on experimental studies, as well as studies of the ex-vivo human lung, pulmonary edema fluid clearance from the alveolar space can be augmented by both inhaled and systemic beta2-adrenoceptor agonists (beta2-agonists). Additionally, in the presence of lung injury, beta2-agonists may reduce lung vascular permeability. Treatment with beta2-agonists may also increase the secretion of surfactant and have anti-inflammatory effects. In view of these potentially beneficial effects, beta2-agonist therapy should be evaluated for the treatment of lung injury in humans, particularly because they are already in wide clinical use and do not seem to have serious adverse effects in critically ill patients.