Pathogenesis Of Adult Respiratory Distress Syndrome Research Articles

IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca2+ uptake during hypocapnia

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

Epithelial and endothelial damage induced by mechanical ventilation modes

The adult respiratory distress syndrome (ARDS) is a common cause of respiratory failure with substantial impact on public health. Patients with ARDS generally require mechanical ventilation, which risks further lung damage. Recent improvements in ARDS outcomes have been attributed to reductions in deforming stress associated with lung protective mechanical ventilation modes and settings. The following review details the mechanics of the lung parenchyma at different spatial scales and the response of its resident cells to deforming stress in order to provide the biologic underpinnings of lung protective care. Although lung injury is typically viewed through the lens of altered barrier properties and mechanical ventilation-associated immune responses, in this review, we call attention to the importance of heterogeneity and the physical failure of the load bearing cell and tissue elements in the pathogenesis of ARDS. Specifically, we introduce a simple elastic network model to better understand the deformations of lung regions, intra-acinar alveoli and cells within a single alveolus, and consider the role of regional distension and interfacial stress-related injury for various ventilation modes. Heterogeneity of stiffness and intercellular and intracellular stress failure are fundamental components of ARDS and their development also depends on the ventilation mode.

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.

Post-hemorrhagic shock mesenteric lymph lipids prime neutrophils for enhanced cytotoxicity via phospholipase A2.

Hemorrhagic shock induced mesenteric hypoperfusion has long been implicated as a key event in the pathogenesis of the adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). Previous work links post-hemorrhagic shock mesenteric lymph (PHSML) lipids and neutrophil (PMN) priming in the pathogenesis of ARDS. We hypothesize that gut phospholipase A2 (PLA2) liberates proinflammatory lipids following hemorrhagic shock, which are responsible for enhanced PMN cytotoxicity. Mesenteric lymph was collected from rats (n > or = 5) before hemorrhagic shock, during hemorrhagic shock (MAP 40 mm Hg x 30 min), and after resuscitation (shed blood + 2x lactated Ringers). PMNs were incubated with physiologic concentrations (1-5%, v:v) of (a) buffer control, (b) sham (c) pre-shock lymph, (c) PHSML, (d) PHSML lipid extracts, (e) heat-denatured PSHML, and (f) PHSML harvested after i.v. pretreatment with a known PLA2 inhibitor (quinacrine, 10 mg/kg). PMNs were activated with fMLP (1 micromol), and the maximal rate of superoxide production measured by reduction of cytochrome c. Gut morphology was assessed histologically using hematoxalin and eosin (HE) staining. PHSML and PHSML lipid extracts (5%, v:v) primed for enhanced superoxide production compared to buffer controls (2.5-fold and 3.6-fold), sham (2.5-fold) and pre-shock lymph (2.0-fold). Lymph collected after systemic PLA2 inhibition, in contrast, abrogated the PMN priming response. Gut mucosal morphology, at end-resuscitation, was intact on HE staining both with and without PLA2 inhibition. Heat denaturing the PHSML (eliminating cytokines and complement), on the other hand, did not reduce PMN priming. Physiologic concentrations of PHSML lipids prime the PMN respiratory burst. Lymph priming is diminished with systemic PLA2 inhibition, implicating gut PLA2 as a source of proinflammatory lipids that may be central in the pathogenesis of hemorrhagic shock induced ARDS/MOF.

The novel chemokine mob-1: Involvement in adult respiratory distress syndrome

Background. Using differential display reverse transcriptase-polymerase chain reaction we have recently identified mob-1, the novel rat homologue of the human α-chemokine IP-10, as a highly inducible gene in adult respiratory distress syndrome (ARDS) lungs. The present study aimed to further implicate mob-1 in the pathogenesis of ARDS. Methods. Pulmonary mob-1 mRNA up-regulation was confirmed by Northern blot analysis in three different rat models of ARDS-like lung injury and localized to pulmonary macrophages by using in situ hybridization. Also, Escherichia coli-derived recombinant mob-1 (rmob-1) was tested for its properties in relationship to lung injury. Results. In vivo, intratracheal injection of rmob-1 (50 μg/rat) induced pulmonary leukosequestration (myeloperoxidase +93% ± 8% versus control, p < 0.05) with preferential accumulation of neutrophils in bronchoalveolar lavage fluid (36.0% ± 1.0% versus 0.1% ± 0.1% in controls, p < 0.01). In vitro, transwell migration studies demonstrated chemotactic activity of rmob-1 (50 to 100 ng/ml) toward human monocytes (+151% ± 34% versus rmob-1 vehicle, p < 0.01) and only weak chemotaxis for human neutrophils (+15% ± 0% versus rmob-1 vehicle, p < 0.01). Utilizing a rat aortic ring model ex vivo, rmob-1 at 100 ng/ml exerted a very potent inhibitory effect on angiogenesis (−78.7% ± 6.3% versus rmob-1 vehicle, p < 0.01), a major component of the resolution phase of ARDS. Conclusions. Taken together, these data support the involvement of mob-1 in the pathogenic mechanisms of ARDS possibly through chemotactic actions on inflammatory cells and modulation of angiogenesis in the recovery phase of the disease.

Nitric oxide attenuates platelet-activating factor priming for elastase release in human neutrophils via a cyclic guanosine monophosphate-dependent pathway

Background. Nitric oxide (NO) has proven benefits in treating adult respiratory distress syndrome (ARDS). The protective mechanism remains unclear, but cyclic guanosine monophosphate (cGMP)-dependent signal transduction pathways have been suggested. Our laboratory has implicated polymorphonuclear neutrophil (PMN) priming and subsequent activation in the pathogenesis of postinjury ARDS and has shown that NO inhibits superoxide anion production from activated PMNs. More recently, the pivotal role of elastase in PMN-mediated tissue injury has been emphasized. Consequently, our study hypothesis was that NO attenuates platelet-activating factor (PAF) priming for elastase release through a cGMP-dependent pathway in human PMNs. Methods. PMNs isolated from human volunteers were preincubated with the NO donor 3-morpholinosydnonimine hydrochloride (SIN-1; 10 −6 to 10 −2 mol/L), cGMP (10 −3 mol/L), or the cell-permeable cGMP analog dibutyryl-cGMP (10 −3 mol/L) for 10 minutes. The cells were then primed with platelet-activating factor (PAF) 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (200 nmol/L), which was followed by N-formyl-methionyl-leucyl-phenylalanine (fMLP) activation (1 μmol/L). Elastase release was measured by the cleavage of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (AAPV-pNA). Results. NO (through SIN-1) significantly attenuated elastase release from PAF-primed PMNs in a dose-dependent manner. Cell-permeable dibutyryl-cGMP attenuated PMN elastase release similar to NO, but cGMP (not cell-permeable) had no effect. Conclusions. NO attenuates elastase release from PAF-primed PMNs through an intracellular cGMP-dependent signal transduction pathway. These findings may partially explain the beneficial effects of NO in the treatment of postinjury ARDS and add to our knowledge of the complex intracellular pathways involved in NO/PMN interactions.

Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.

This study was designed to investigate possible involvement of type IV collagenolytic matrix metalloproteinases (MMPs; 72-kDa type IV collagenase [MMP-2], 92-kDa type IV collagenase [MMP-9]), and the respective specific tissue inhibitors of these MMPs (TIMP-2 and TIMP-1) in the development of adult respiratory distress syndrome (ARDS). We determined the concentrations of these enzymes in the bronchoalveolar lavage fluid (BALF) from patients with ARDS using newly developed sensitive one-step sandwich enzyme immunoassay methods. BALF obtained from the 17 patients and eight healthy volunteer control subjects were also used for the analysis of the number of the cellular component. Concentrations of the 7S portion of type IV collagen and laminin in the BALF were measured as markers of basement membrane disruption. In the BALF from the ARDS patients, the concentrations of MMP-2 (66.7 +/- 57.0 ng/ml versus < 7.0 ng/ml for controls, p < 0.01) and MMP-9 (118.0 +/- 309.3 ng/ml versus 9.0 +/- 9.5 ng/ml for controls, p < 0.05), and the specific inhibitor of MMP-9 (TIMP-1) (161.0 +/- 145.0 ng/ml versus < 50 ng/ml for controls, p < 0.01) were significantly higher compared with those for healthy control subjects. In the ARDS patients, the concentrations of MMP-2 correlated both with those of 7S collagen and laminin; MMP-9 with the concentration of 7S collagen and the number of neutrophils. These findings suggest that the increased concentration of collagenolytic MMPs in lung plays a role in the pathogenesis of ARDS.

HIGH LEVELS OF LEUKAEMIA INHIBITORY FACTOR IN ARDS

Although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (BAL) fluid (BALF) of patients with the acute (adult) respiratory distress syndrome (ARDS), the pathogenesis of ARDS is largely unknown. Leukaemia inhibitory factor (LIF), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated BALF of patients from different patient groups. LIF was measured in BALF by means of a specific and sensitive ELISA (detection limit 10 pg/ml) in BALF (lavage of 3 x 50 ml in the right middle lobe). LIF was not detected in the BALF of 13 healthy control patients and in only one (34 pg/ml) out of 25 patients at risk for ARDS (after cardiopulmonary bypass surgery) who underwent BAL 4 h after the end of the extracorporeal circulation. High and detectable levels were found in the unconcentrated BALF of 10 out of 12 patients with full-blown ARDS (212 ± 116, mean ± SEM, range 10–985 pg/ml). There was a good correlation between the level of LIF in the BALF and a number of markers of inflammation such as neutrophils/ml, albumin and protein levels. The biological role of LIF in these BALFs is not readily explained by its currently known actions and it is unknown whether LIF contributes to or is a response to local tissue damage. Our results indicate that this cytokine is part of the inflammatory cytokine cascade in ARDS.

The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome.

To determine the relation between 1) intra-alveolar concentrations of the proinflammatory cytokines (tumor necrosis factor, interleukin-1 beta, and interleukin-8) and the anti-inflammatory cytokines (interleukin-10 and interleukin-1 receptor antagonist) in patients with early adult respiratory distress syndrome (ARDS) and 2) subsequent patient mortality rates. Prospective cohort study. University medical center. 28 consecutive patients in whom ARDS was prospectively identified during hospitalization and 9 ventilated controls. Concentrations of proinflammatory cytokines and anti-inflammatory cytokines in bronchoalveolar lavage fluid. The concentrations of proinflammatory and anti-inflammatory cytokines within the alveolar air spaces were significantly elevated in patients with ARDS compared with controls (P = 0.01 for tumor necrosis factor [median, 90 pg/mL (range, 0 to 2500 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 118 pg/mL) for controls]; P = 0.001 for interleukin-1 beta [median, 179 pg/mL (range, 0 to 2200 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 80 pg/mL) for controls]; P = 0.0001 for interleukin-8 [median, 628 pg/mL (range, 0 to 4700 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 278 pg/mL) for controls]; P = 0.0005 for interleukin-10 [median, 100 pg/mL (range, 0 to 1600 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 50 pg/mL) for controls], and P = 0.002 for interleukin-1 receptor antagonist [median, 820 pg/mL (range, 0 to 18,900 pg/mL) for patients with ARDS; median, 50 pg/mL (range, 0 to 240 pg/mL) for controls]). A highly significant correlation was found between low concentrations of anti-inflammatory cytokines and subsequent patient mortality rates (P = 0.003 for interleukin-10 [median, 120 pg/mL (range, 30 to 1600 pg/mL) for survivors; median, 40 pg/mL (range, 0 to 110 pg/mL) for nonsurvivors]; P = 0.008 for interleukin-1 receptor antagonist [median, 1600 pg/mL (range, 80 to 18,900 pg/mL) for survivors; median, 90 pg/mL (range, 0 to 3400 pg/mL) for nonsurvivors. No significant correlation was found between the concentrations of the proinflammatory cytokines and mortality rates. Low concentrations of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist in bronchoalveolar lavage fluid obtained from patients with early ARDS are closely associated with poor prognosis. These findings support the hypothesis that failure to mount a localized intrapulmonary anti-inflammatory response early in the pathogenesis of ARDS contributes to more severe organ injury and worse prognosis. Our findings suggest that augmenting anti-inflammatory cytokine defenses would be a beneficial therapeutic approach to patients with ARDS and other inflammatory diseases.

The Role of Tumor Necrosis Factor-α and Interleukin-1β as Predictable Markers for Development of Adult Respiratory Distress Syndrome in Septic Syndrome

Background Tumor necrosis factor(TNF)-α and Interleukin(IL)-1β are thought to play a major role in the pathogenesis of the septic syndrome, which is frequently associated with adult respiratory distress syndrome(ARDS). In spite of many reports for the role of TNF-α in the pathogenesis of ARDS, including human studies, it has been reported that TNF-α is not sensitive and specific marker for impending ARDS. But there is a possibility that the results were affected by the diversity of pathogenetic mechanisms leading to the ARDS because of various underlying disorders of the study group in the previous reports. The purpose of the present study was to evaluate the roles of TNF-α and IL-lβ as a predictable marker for development of ARDS in the patients with septic syndrome, in which the pathogenesis is believed to be mainly cytokine-mediated. Methods Thirty-six patients of the septic syndrome hospitalized in the intensive care units of the Asan Medical Center were studied. Sixteens suffered from ARDS, whereas the remaining 20 were at the risk of developing ARDS(acute hypoxemic respiratory failure, AHRF). In all patients venous blood sample were collected in heparin-coated tubes at the time of enrollment, at 24 and 72 h thereafter. TNF-α and IL-lβ was measured by an enzyme-linked immunosorbent assay (ELISA). All data are expressed as median with interquartile range. Results 1) Plama TNF-α levels: Plasma TNF-β levels were less than 10pg/mL, which is lowest detection value of the kit used in this study within the range of the mean±2SD, in all of the normal controls, 8 of 16 subjects of ARDS and in 8 in 20 subjects of AHRF. Plasma TNF-α levels from patients with ARDS were 10.26pg/mL(median;<10-16.99pg/mL, interquartile range) and not different from those of patients at AHRF(10.82, <10-20.38pg/mL). There was also no significant difference between pre-ARDS(<10, <10-15.32pg/mL) and ARDS(<10, <10-10.22pg/mL). TNF-α levels were significantly greater in the patients with shock than the patients without shock(12.53pg/mL vs. <10pg/mL) (P<0.01). There was no statistical significance between survivors(< 10, <10-12.92pg/mL) and nonsurvivors(11.80, <10-20.8pg/mL) (P=0.28) in the plasma TNF-α levels. 2) Plasma IL-lβ levels: Plasma IL-1β levels were less than 0.3ng/mL, which is the lowest detection value of the kit used in this study, in one of each patients group. There was no significant difference in IL-1β levels of the ARDS(2.22, 1.37-8.01ng/mL) and of the AHRF(2.13, 0.83-5.29ng/mL). There was also no significant difference between pre-ARDS(2.53, <0.3-8.34ng/mL) and ARDS(5.35, 0.66-11.51ng/mL), and between patients with septic shock and patients without shock (2.51, 1.28-8.34 vs 1.46, 0.15-2.13ng/mL). Plasma IL-19 levels were significantly different between survivors(1.37, 0.4-2.36ng/mL) and nonsurvivors(2.84, 1.46-8.34ng/mL). Conclusion Plasma TNF-α and IL-1β level are not a predictable marker for development of ARDS. But TNF-α is a marker for shock in septic syndrome. These result could not exclude a possibility of pathophysiologic roles of TNF-α and IL-1β in acute lung injury because these cytokine could be locally produced and exert its effects within the lungs.

High levels of interleukin-8 in the blood and alveolar spaces of patients with pneumonia and adult respiratory distress syndrome.

There is ample experimental evidence that polymorphonuclear neutrophils (PMN) play a critical role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Since interleukin-8 (IL-8) is a strong chemotactic factor for PMN, we measured IL-8 levels in plasma and bronchoalveolar lavage (BAL) fluid of 18 patients, 12 with ARDS and 6 with severe pneumonia uncomplicated by ARDS, all of whom had an increased number of PMN in BAL fluid. Seven healthy subjects served as controls. We found elevated levels of IL-8 in the alveolar spaces of all patients tested. Elevated BAL IL-8 levels were related to a fatal outcome and the presence of shock and correlated with a general clinical severity index (simplified acute physiological score). BAL fluid levels of IL-8 were significantly higher in patients with ARDS than in patients with pneumonia. In plasma, IL-8 levels were increased similarly in all patients and did not correlate with survival or the presence of shock. The BAL fluid-to-plasma ratio of IL-8 was significantly greater than that of tumor necrosis factor alpha, indicating higher local production of IL-8. Moreover, the presence of a primed subpopulation of blood PMN with respect to H2O2 production indicates that IL-8 may contribute to the neutrophil-mediated process in the pathogenesis of ARDS and pneumonia.

In vitro studies on PMN-independent endothelial cell damage in trauma: decrease of PMN-endothelial cell adherence by fibrinogen degradation products and disturbance of endothelial cell membrane integrity by trauma serum.

Trauma favors the development of adult respiratory distress syndrome (ARDS). Adherence of polymorphonuclear leukocytes (PMN) to endothelial cells (EC) with subsequent EC damage by the respiratory burst products and proteases of the PMN is thought to be one of the basic mechanisms in the pathogenesis of ARDS. Recent studies have shown that there might also be PMN-independent mechanisms of EC damage. It would speak for PMN-independent EC damage if in the state of risk for this damage factors were found which decrease PMN activity or if EC damage appeared without PMN. Because in trauma and sepsis pathologic coagulation with high levels of fibrinogen degradation products (FDP) is often diagnosed, we investigated whether FDP-D and FDP-E might influence PMN adherence to EC. We also investigated whether serum of traumatized patients might provoke EC damage in a PMN-independent system in vitro. To achieve this we evaluated the viability of EC using a fluorescence staining method. We found that both FDP-D and FDP-E decreased PMN adherence to human EC significantly (p < 0.01) at a concentration of 50 micrograms/ml. Furthermore we found that EC membrane integrity can be disturbed by serum of trauma patients. These results suggest that in trauma also PMN-independent mechanisms are important for EC damage.

The Rat Lung Organotypic Culture

The amount of surfactant present in the intra-alveolar space is mainly regulated by the synthesis and recycling of surfactant by type II pneumocytes. Biochemical analyses have shown that the surfactant level is frequently diminished and that protein-rich exudate can further interfere with surfactant function in the lungs of adult respiratory distress syndrome (ARDS) patients. The microenvironmental changes that occur in the alveoli of burned patients, who are prone to developing ARDS, are unclear. Therefore, using an in vitro rat lung organotypic culture, we showed that the sera of rats with a 3-day old, third-degree thermal injury (25-30% total body surface area) inhibited surfactant synthesis in organotypically cultured rat lung cells. Surfactant precursor, 3H-choline, incorporation into the surfactant was 58% of control. Using liposomes made of dipalmitoyl phosphatidylcholine and phosphatidylglycerol (8:1, v/v) or surfactant we showed that surfactant endocytosis by purified type II alveolar cells is an active, temperature-dependent process, and correlates with the quantity of surfactant present in the milieu. We also found that plasma protein-rich fluid interfered with surfactant endocytosis by the purified type II pneumocytes. These two processes of inhibition of surfactant synthesis and its reutilization by these cells may contribute to the pathogenesis of ARDS.

The Rat Lung Organotypic Culture

The amount of surfactant present in the intra-alveolar space is mainly regulated by the synthesis and recycling of surfactant by type II pneumocytes. Biochemical analyses have shown that the surfactant level is frequently diminished and that protein-rich exudate can further interfere with surfactant function in the lungs of adult respiratory distress syndrome (ARDS) patients. The microenvironmental changes that occur in the alveoli of burned patients, who are prone to developing ARDS, are unclear. Therefore, using an in vitro rat lung organotypic culture, we showed that the sera of rats with a 3-day old, third-degree thermal injury (25-30% total body surface area) inhibited surfactant synthesis in organotypically cultured rat lung cells. Surfactant precursor, 3H-choline, incorporation into the surfactant was 58% of control. Using liposomes made of dipalmitoyl phosphatidylcholine and phosphatidylglycerol (8:1, v/v) or surfactant we showed that surfactant endocytosis by purified type II alveolar cells is an active, temperature-dependent process, and correlates with the quantity of surfactant present in the milieu. We also found that plasma protein-rich fluid interfered with surfactant endocytosis by the purified type II pneumocytes. These two processes of inhibition of surfactant synthesis and its reutilization by these cells may contribute to the pathogenesis of ARDS.

Functional and Metabolic Activity of Polymorphonuclear Leukocytes from Patients with Adult Respiratory Distress Syndrome

Indirect and experimental evidence suggests that polymorphonuclear leukocytes, responding to an activating signal presumably related to the complement cascade activation, are involved in the pathogenesis of the adult respiratory distress syndrome (ARDS). The pathologic changes seem to be result of the polymorphonuclear leukocyte margination within the pulmonary capillary vessels and their activation with subsequent release of vasoactive peptides (thromboxane A2, prostaglandin E2) and toxic intracellular compounds. This study confirms that adherence, chemotaxis, and chemiluminescence are increased in polymorphonuclear leukocytes from patients with ARDS. Enhanced chemotactic and chemiluminescence capacities are likely specific to ARDS, whereas increased polymorphonuclear leukocyte adherence seems to be nonspecific. If increased polymorphonuclear leukocyte activation is important in the pathogenesis of ARDS, the inhibition of this phenomenon could play a therapeutic role. This double-blind prospective study was undertaken to assess if polymorphonuclear leukocyte activity is inhibited in vivo by the iv administration of prostaglandin E1 (PGE1) in patients with ARDS. A continuous infusion of PGE1 at a dose of 30 ng.kg-1.min-1 for 7 days did not modify the functional activity of polymorphonuclear leukocytes in patients with ARDS. Because hemodynamic instability was seen during infusion of this dose of PGE1, an increased dose was not tested. At the dose of PGE1 tested, no significant effect upon the function activity of polymorphonuclear leukocytes in patients with ARDS could be demonstrated.

Southwestern Internal Medicine Conference: Adult Respiratory Distress Syndrome

The Adult Respiratory Distress Syndrome (ARDS) is a fulminant form of respiratory failure affecting many seriously ill patients. The early manifestations of ARDS are caused by increased permeability of the alveolo-capillary barrier leading to pulmonary edema, stiff lungs, and a large right-to-left intrapulmonary shunt. Polymorphonuclear leukocytes (PMNS) are involved in the pathogenesis of most ARDS, and multiple PMN mechanisms can effect pulmonary injury; interactions between PMN adherence, proteolytic enzyme release, and oxygen radical production are emphasized. ARDS therapy remains largely supportive and has had little impact on mortality. The complications of infection and multiorgan failure play important roles in determining ARDS outcome.

Increased Hydrogen Peroxide in the Expired Breath of Patients with Acute Hypoxemic Respiratory Failure

Acute hypoxemic respiratory failure (AHRF) can result from diverse lung insults. Toxic oxygen metabolites have been implicated in this clinical condition and in animal models of pulmonary edema. Hydrogen peroxide (H2O2), an oxygen metabolite, mediates tissue injury. We measured H2O2 levels by a spectrophotometric technique in the breath condensate of 68 mechanically ventilated patients; 13 patients with normal lungs undergoing elective surgery had no such detectable levels of H2O2. Fifty-five patients in the ICU meeting criteria for the adult respiratory distress syndrome (ARDS) had a higher concentration of H2O2 in the expired breath condensate than ICU patients without pulmonary infiltrates (2.34 +/- 1.15 vs 0.99 +/- 0.72 mumol/L, p less than 0.005). This marker had a sensitivity of 87.5 percent and a specificity of 81.3 percent in separating the two patient populations. Patients with AHRF and focal pulmonary infiltrates who did not meet criteria for ARDS also had higher concentrations of H2O2 (2.45 +/- 1.55 mumol/L) than patients without pulmonary infiltrates (p less than 0.001). No difference was observed between the expired H2O2 concentrations of patients with ARDS or patients with focal pulmonary infiltrates. Patients with brain injury or sepsis tended to have higher levels of H2O2 regardless of lung pathology. Increased levels of H2O2 are detected in the expired breath of ICU patients with focal lung infiltrates and in ARDS patients, which is consistent with the hypothesis that oxygen metabolites participate in the pathogenesis of ARDS and other forms of AHRF.

Fibrinolysis in Critically III Patients

Impaired fibrinolysis may contribute to development of adult respiratory distress syndrome (ARDS). Pathologic increases in endogenous plasminogen activator inhibitor (PAI-1) may blunt normal fibrinolysis and unmask alternate fibrinolytic mechanisms, such as elastase-induced fibrin degradation. We measured PAI-1 and elastase-induced fibrin(ogen) degradation products in 69 critically ill patients in our medical intensive care unit (MICU) and in nine healthy volunteers. Factor VIII-related antigen protein (VIII:Ag), a reported marker of acute lung injury, and alpha-1-protease inhibitor (alpha-1-PI), an acute phase reactant, were also measured. MICU patients included 24 control patients with no known risk of ARDS, 35 patients with risk factors for ARDS including sepsis, pneumonia, aspiration, and shock, and 12 patients with ARDS including two patients from at-risk groups who developed ARDS. Plasma PAI-1 was determined by chromogenic assay, elastase-induced peptides by a new radioimmunoassay, VIII:Ag by immunoelectrophoresis, and alpha-1-PI by immunodiffusion. When compared to normal volunteers, MICU control patients had elevated PAI-1, VIII:Ag, elastase-induced peptides, and alpha-1-PI. Patients with ARDS had significantly higher PAI-1 and VIII:Ag than did MICU control patients; elastase-induced peptides and alpha-1-PI were not higher. However, at-risk patients who did not develop ARDS also had high PAI-1 or VIII:Ag. Although these data cannot refute the possible role of these compounds in the pathogenesis of ARDS, they demonstrate that PAI-1 and VIII:Ag may be elevated in many critically ill patients but may not be useful markers for the subsequent development of ARDS.

OXIDANT ACTIVITY IN EXPIRED BREATH OF PATIENTS WITH ADULT RESPIRATORY DISTRESS SYNDROME

Hydrogen peroxide levels were measured in the breath condensate of 43 patients receiving mechanical ventilation. In 16 patients the mean breath condensate peroxide level was 1·68±0·35 μmol/l on the day they met diagnostic criteria for adult respiratory distress syndrome (ARDS). The peak breath condensate peroxide level in the 27 patients in whom ARDS did not develop was significantly lower (0·34±0·08 μmol/l). Plasma lysozyme, a measure of in-vivo neutrophil turnover, was significantly higher in ARDS than in non-ARDS patients (9·2±2·2 U/ml v 3·4±1·1 U/ml). These findings support the hypothesis that neutrophil activation and oxidant production are involved in the pathogenesis of ARDS.

Oxygen-free radicals and lipid peroxidation in adult respiratory distress syndrome.

Activated species of oxygen have been implicated as mediators of some acute lung injury. In adult respiratory distress syndrome (ARDS), polymorphonuclear leukocytes accumulate in the lung and release excessive amounts of O2-derived products into the extracellular environment. The effects of these O2 products on lung tissue are multiple. In particular, they can initiate lipid peroxydation in cellular membranes. Excessive lipid peroxydation in membranes destroys cells such as vascular endothelium. Lipid peroxides are also detrimental to cellular functions. Lipid peroxydation could then play a role in the pathogenesis of ARDS.