Lung Vascular Hyperpermeability Research Articles

Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction

BackgroundObesity has been identified as a risk factor for acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the underlying mechanisms remain elusive. This study aimed to investigate the role of fatty acid synthase (FASN) in lipopolysaccharide (LPS)-induced ALI under obesity.MethodsA high-fat diet-induced obese (DIO) mouse model was established and lean mice fed with regular chow diet were served as controls. LPS was intratracheally instilled to reproduce ALI in mice. In vitro, primary mouse lung endothelial cells (MLECs), treated by palmitic acid (PA) or co-cultured with 3T3-L1 adipocytes, were exposed to LPS. Chemical inhibitor C75 or shRNA targeting FASN was used for in vivo and in vitro loss-of-function studies for FASN.ResultsAfter LPS instillation, the protein levels of FASN in freshly isolated lung endothelial cells from DIO mice were significantly higher than those from lean mice. MLECs undergoing metabolic stress exhibited increased levels of FASN, decreased levels of VE-cadherin with increased p38 MAPK phosphorylation and NLRP3 expression, mitochondrial dysfunction, and impaired endothelial barrier compared with the control MLECs when exposed to LPS. However, these effects were attenuated by FASN inhibition with C75 or corresponding shRNA. In vivo, LPS-induced ALI, C75 pretreatment remarkably alleviated LPS-induced overproduction of lung inflammatory cytokines TNF-α, IL-6, and IL-1β, and lung vascular hyperpermeability in DIO mice as evidenced by increased VE-cadherin expression in lung endothelial cells and decreased lung vascular leakage.ConclusionsTaken together, FASN inhibition alleviated the exacerbation of LPS-induced lung injury under obesity via rescuing lung endothelial dysfunction. Therefore, targeting FASN may be a potential therapeutic target for ameliorating LPS-induced ALI in obese individuals.

Interleukin-1RA Mitigates SARS-CoV-2-Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice.

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Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury.

Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.

Possible involvement of VEGF in sepsis-associated lung vascular hyperpermeability

Possible involvement of VEGF in sepsis-associated lung vascular hyperpermeability

Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions

Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as capillary "stress failure" that causes leakage of protein-rich plasma and pulmonary edema. However, little is known about vascular endothelial sensing and transduction of mechanical stimuli inducing endothelial barrier disruption. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), is activated by elevated pressure and other mechanical stimuli. Here, we demonstrate the involvement of Piezo1 in sensing increased lung microvessel pressure and mediating endothelial barrier disruption. Studies were made in mice in which Piezo1 was deleted conditionally in ECs (Piezo1iΔEC ), and lung microvessel pressure was increased either by raising left atrial pressure or by aortic constriction. We observed that lung endothelial barrier leakiness and edema induced by raising pulmonary microvessel pressure were abrogated in Piezo1iΔEC mice. Piezo1 signaled lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherens junction (AJ) protein VE-cadherin. Breakdown of AJs was the result of activation of the calcium-dependent protease calpain and degradation of the AJ proteins VE-cadherin, β-catenin, and p120-catenin. Deletion of Piezo1 in ECs or inhibition of calpain similarly prevented reduction in the AJ proteins. Thus, Piezo1 activation in ECs induced by elevated lung microvessel pressure mediates capillary stress failure and edema formation secondary to calpain-induced disruption of VE-cadherin adhesion. Inhibiting Piezo1 signaling may be a useful strategy to limit lung capillary stress failure injury in response to elevated vascular pressures.

Propofol Protects Lung Endothelial Barrier Function by Suppression of High-Mobility Group Box 1 (HMGB1) Release and Mitochondrial Oxidative Damage Catalyzed by HMGB1.

BackgroundThe processes of mechanical ventilation-induced lung injury (VILI) triggers the release of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern (DAMP) family member, which can cause damage to pulmonary vascular endothelial cells. We aimed to determine whether propofol protected against endothelial cell injury induced by HMGB1 in vitro and in vivo.Material/MethodsICR mice (male) were mechanically ventilated for 4 h after anesthetization at both low tidal volume (LVT, 6 ml/kg) and high tidal volume (HVT, 30 ml/kg). A propofol bolus (10 mg/kg) was administered to the animals prior to the onset of ventilation, followed by infusion at 5 mg/(kg·h). We obtained confluent cultures of mouse lung vascular endothelial cells (MLVECs) and then performed cyclic stretching at 20% stretch for 4 h with or without propofol.ResultsHMGB1 reduced the expression of tight junctions between endothelial cells, including VE-cadherin and ZO-1, and increased endothelial permeability, and both were blocked by propofol. We found that MLVECs exhibited mitochondrial oxidative damage by HMGB1, which was successfully suppressed through administration of MnTBAP as well as propofol. Propofol ameliorated HVT-associated lung vascular hyperpermeability and HMGB1 production in vivo. Propofol also inhibited HMBG1 release caused by cyclic stretching in MLVECs in vitro.ConclusionsOur results prove that the cyto-protective function of propofol protects against lung ventilation-induced dysfunction of the lung endothelial barrier. This function of propofol is mediated through inhibition of HMGB1 release caused by mechanical stretching and mitochondrial oxidative damage triggered by HMGB1.

Myosin Light Chain Kinase‐210 Induces ER‐PM Junctions and STIM1 Puncta Formation to Augment Store‐Operated Ca2+ Entry

Myosin light chain kinase‐Long (MYLK‐L or MYLK‐210), a Ca2+‐calmodulin dependent kinase containing a unique 922‐amino acid N‐terminal domain is a predominant isoform of MYLK expressed in endothelial cells (ECs). N‐terminus of MYLK‐210 has been shown to contain several single nucleotide polymorphisms (SNPs) in an actin binding region which is associated with severity of acute lung injury (ALI). However, significance of SNPs in regulating MYLK‐210 function remains unclear. The classical function of MYLK‐210 is to catalyze the phosphorylation of myosin light chain to induce EC contraction, leading to inter‐endothelial gap formation and increase permeability, a hall mark of ALI. Intriguingly, we showed that MYLK‐210, through its actin‐binding motif, regulates store‐operated Ca2+ entry (SOCE) but not receptor‐operated Ca2+ entry (ROCE). We showed that MYLK‐210 null endothelial cells (ECs) or MYLK‐210 depleted ECs displayed diminished Ca2+ entry in response to SOCE‐activator thapsigargin and thrombin. We generated MYLK‐210 constructs lacking C‐terminus (N‐MYLK) or N‐terminus (C‐MYLK) to investigate the role of specific domains of MYLK‐210 in inducing SOCE activity. We found that N‐MYLK but not C‐MYLK rescued SOCE activity in MYLK‐210 null ECs, indicating thereby that MYLK regulates SOCE in a kinase independent manner. Additionally, SOCE activation failed to increase lung vascular hyper‐permeability in MYLK‐210 null mice. We identified unique actin binding motif, DVRGLL within N terminus of MYLK‐L which enables MYLK‐210 to induce SOCE. Stromal‐interaction molecule 1 (STIM1), upon sensing the depletion of (Ca2+) from the endoplasmic reticulum (ER) store, organizes as puncta which translocate to plasma membrane that trigger SOCE via plasmalemmal Ca2+selective channels such as transient receptor potential channel 1 (TRPC1) and Orai1. Thus, we addressed if MYLK‐L controlled STIM1 function by regulating puncta formation. We showed that STIM1 formed puncta in control ECs but these puncta were markedly reduced in MYLK depleted ECs. Formation of endoplasmic reticulum (ER)‐plasma membrane (PM) junction is required for STIM1 activation of SOCE. Using MAPPER (membrane‐attached peripheral ER) that selectively labels ER–PM junctions, we found that MYLK induced ER‐PM junction, but these junctions were markedly reduced in the density in MYLK‐knockdown cells. Our study thereby defines for the first time the clinical validity of SNPs within actin binding region of MYLK in inducing ALI through organizing ER‐PM junctions, STIM1 activity, SOCE and lung vascular hyperpermeability.Support or Funding InformationNational Institute of Health (NIH)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism

High-mobility group box 1 (HMGB1) contributes to lung vascular hyperpermeability during ventilator-induced lung injury. We aimed to determine whether the natural antioxidant resveratrol protected against HMGB1-induced endothelial hyperpermeability both in vitro and in vivo. We found that HMGB1 decreased vascular endothelial (VE)-cadherin expression and increased endothelial permeability, leading to mitochondrial oxidative damage in primary cultured mouse lung vascular endothelial cells (MLVECs). Both the mitochondrial superoxide dismutase 2 mimetic MnTBAP and resveratrol blocked HMGB1-induced mitochondrial oxidative damage, VE-cadherin downregulation, and endothelial hyperpermeability. In in vivo studies, anesthetized male ICR mice were ventilated for 4h using low tidal volume (6ml/kg) or high tidal volume (HVT; 30ml/kg) ventilation. The mice were injected intraperitoneally with resveratrol immediately before the onset of ventilation. We found that resveratrol attenuated HVT-associated lung vascular hyperpermeability and HMGB1 production. HVT caused a significant increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and Nrf2 target gene expression in lung tissues, which was further enhanced by resveratrol treatment. HMGB1 had no effect on Nrf2 activation, whereas resveratrol treatment activated the Nrf2 signaling pathway in HMGB1-treated MLVECs. Moreover, Nrf2 knockdown reversed the inhibitory effects of resveratrol on HMGB1-induced mitochondrial oxidative damage and endothelial hyperpermeability. The inhibitory effect of resveratrol on cyclic stretch-induced HMGB1 mRNA expression in primary cultured MLVECs was also abolished by Nrf2 knockdown. In summary, this study demonstrates that resveratrol protects against lung endothelial barrier dysfunction initiated by HVT. Lung endothelial barrier protection by resveratrol involves inhibition of mechanical stretch-induced HMGB1 release and HMGB1-induced mitochondrial oxidative damage. These protective effects of resveratrol might be mediated through an Nrf2-dependent mechanism.

Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation

Isthmin (ISM) is a recently identified 60 kDa secreted angiogenesis inhibitor. Two cell-surface receptors for ISM have been defined, the high-affinity glucose-regulated protein 78 kDa (GRP78) and the low-affinity αvβ5 integrin. As αvβ5 integrin plays an important role in pulmonary vascular permeability (VP) and ISM is highly expressed in mouse lung, we sought to clarify the role of ISM in VP. Recombinant ISM (rISM) dose-dependently enhances endothelial monolayer permeability in vitro and local dermal VP when administered intradermally in mice. Systemic rISM administration through intravenous injection leads to profound lung vascular hyperpermeability but not in other organs. Mechanistic investigations using molecular, biochemical approaches and specific chemical inhibitors revealed that ISM-GRP78 interaction triggers a direct interaction between GRP78 and Src, leading to Src activation and subsequent phosphorylation of adherens junction proteins and loss of junctional proteins from inter-endothelial junctions, resulting in enhanced VP. Dynamic studies of Src activation, VP and apoptosis revealed that ISM induces VP directly via Src activation while apoptosis contributes indirectly only after prolonged treatment. Furthermore, ISM is significantly up-regulated in lipopolysaccharide (LPS)-treated mouse lung. Blocking cell-surface GRP78 by systemic infusion of anti-GRP78 antibody significantly attenuates pulmonary vascular hyperpermeability in LPS-induced acute lung injury (ALI) in mice. ISM is a novel VP inducer that functions through cell-surface GRP78-mediated Src activation as well as induction of apoptosis. It induces a direct GRP78-Src interaction, leading to cytoplasmic Src activation. ISM contributes to pulmonary vascular hyperpermeability of LPS-induced ALI in mice.

Abstract 15720: Synergistic Effect of Acetylation and Methylation Modifiers in Attenuating Lung Vascular Hyperpermeability in Endotoxemia-Induced Inflammatory Lung Injury

Background: Migration of fluid and inflammatory cells across vascular endothelial barrier is crucial in pathogenesis of acute lung injury (ALI) in sepsis. Currently no treatment can effectively improve the profound dysregulation of lung endothelial barrier in ALI. Hypothesis: We hypothesized that combinatorial treatment with DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine (Aza) and histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) would synergistically preserve lung microvascular endothelial barrier function. Methods and Results: The trans-endothelial electrical resistance (TER) and capillary filtration coefficient (K fc ) data show that in LPS-exposed endothelial cells and mice, therapy with Aza+TSA leads to a significant decrease in lung microvascular permeability as compared with either alone. The ChiP data show that the VE-cadherin promoter region was more acetylated at histone 3 in LPS-induced lung ECs treated with Aza+TSA than either alone. In an ALI mouse model, post-injury treatment with a single dose of Aza+TSA prevented lung injury and afforded a significantly higher survival rate (80%) as compared with mice treated with either Aza or TSA alone. These effects were mediated by a significant attenuation of adverse lung histopathological changes and preservation of endothelial barrier integrity. Aza+TSA also significantly reduced neutrophil infiltration in the ALI model. The RT-PCR array data revealed that 42 inflammation-related miRNAs were differentially expressed in LPS-induced endothelial cells, among which miRNA-92a, 125b, 133a, 146, 214, 222, and 424 were strongly upregulated. Importantly, Aza+TSA treatment significantly reduced the expression of these miRNAs. The protection was ascribed to inhibition of the eNOS-Cav1-MLC2 signaling pathway and enhanced acetylation of histone markers on the VE-cadherin promoter. Conclusions: These data for the first time show the efficacy of synergistic effect of Aza+TSA therapy in preventing ALI in LPS-induced endotoxemia, and raise the possibility of an essential role of DNMT and HDAC in pathogenesis of ALI. This novel combinatorial regimen may improve and prolong the lives of people with ALI.

Cooperative Signaling via Transcription Factors NF-κB and AP1/c-Fos Mediates Endothelial Cell STIM1 Expression and Hyperpermeability in Response to Endotoxin

Stromal interacting molecule 1 (STIM1) regulates store-operated Ca(2+) entry (SOCE). Here we show that STIM1 expression in endothelial cells (ECs) is increased during sepsis and, therefore, contributes to hyperpermeability. LPS induced STIM1 mRNA and protein expression in human and mouse lung ECs. The induced STIM1 expression was associated with augmented SOCE as well as a permeability increase in both in vitro and in vivo models. Because activation of both the NF-κB and p38 MAPK signaling pathways downstream of TLR4 amplifies vascular inflammation, we studied the influence of these two pathways on LPS-induced STIM1 expression. Inhibition of either NF-κB or p38 MAPK activation by pharmacological agents prevented LPS-induced STIM1 expression. Silencing of the NF-κB proteins (p65/RelA or p50/NF-κB1) or the p38 MAPK isoform p38α prevented LPS-induced STIM1 expression and increased SOCE in ECs. In support of these findings, we found NF-κB and AP1 binding sites in the 5'-regulatory region of human and mouse STIM1 genes. Further, we demonstrated that LPS induced time-dependent binding of the transcription factors NF-κB (p65/RelA) and AP1 (c-Fos/c-Jun) to the STIM1 promoter. Interestingly, silencing of c-Fos, but not c-Jun, markedly reduced LPS-induced STIM1 expression in ECs. We also observed that silencing of p38α prevented c-Fos expression in response to LPS in ECs, suggesting that p38α signaling mediates the expression of c-Fos. These results support the proposal that cooperative signaling of both NF-κB and AP1 (via p38α) amplifies STIM1 expression in ECs and, thereby, contributes to the lung vascular hyperpermeability response during sepsis.

Combinatorial Therapy with Acetylation and Methylation Modifiers Attenuates Lung Vascular Hyperpermeability in Endotoxemia-Induced Mouse Inflammatory Lung Injury

Impairment of tissue fluid homeostasis and migration of inflammatory cells across the vascular endothelial barrier are crucial factors in the pathogenesis of acute lung injury (ALI). The goal for treatment of ALI is to target pathways that lead to profound dysregulation of the lung endothelial barrier. Although studies have shown that chemical epigenetic modifiers can limit lung inflammation in experimental ALI models, studies to date have not examined efficacy of a combination of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine and histone deacetylase inhibitor trichostatin A (herein referred to as Aza+TSA) after endotoxemia-induced mouse lung injury. We tested the hypothesis that treatment with Aza+TSA after lipopolysaccharide induction of ALI through epigenetic modification of lung endothelial cells prevents inflammatory lung injury. Combinatorial treatment with Aza+TSA mitigated the increased endothelial permeability response after lipopolysaccharide challenge. In addition, we observed reduced lung inflammation and lung injury. Aza+TSA also significantly reduced mortality in the ALI model. The protection was ascribed to inhibition of the eNOS-Cav1-MLC2 signaling pathway and enhanced acetylation of histone markers on the vascular endothelial-cadherin promoter. In summary, these data show for the first time the efficacy of combinatorial Aza+TSA therapy in preventing ALI in lipopolysaccharide-induced endotoxemia and raise the possibility of an essential role of DNA methyl transferase and histone deacetylase in the mechanism of ALI.

A Critical Role for Phosphatidylinositol (3,4,5)-Trisphosphate–Dependent Rac Exchanger 1 in Endothelial Junction Disruption and Vascular Hyperpermeability

The small GTPase Rac is critical to vascular endothelial functions, yet its regulation in endothelial cells remains unclear. Understanding the upstream pathway may delineate Rac activation mechanisms and its role in maintaining vascular endothelial barrier integrity. By investigating phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 (P-Rex1), one of the Rac-specific guanine nucleotide exchange factors previously known for G protein-coupled receptor signaling, we sought to determine whether Rac-guanine nucleotide exchange factor is nodal for signal integration and potential target for drug intervention. Using gene deletion and small interference RNA silencing approach, we investigated the role of P-Rex1 in human lung microvascular endothelial cells. Tumor necrosis factor α (TNF-α) exposure led to disruption of endothelial junctions, and silencing P-Rex1 protected junction integrity. TNF-α stimulated Rac activation and reactive oxygen species production in a P-Rex1-dependent manner. Removal of P-Rex1 significantly reduced intercellular adhesion molecule-1 expression, polymorphonuclear leukocyte transendothelial migration, and leukocyte sequestration in TNF-α-challenged mouse lungs. The P-Rex1 knockout mice were also refractory to lung vascular hyperpermeability and edema in a lipopolysaccharide-induced sepsis model. These results demonstrate for the first time that P-Rex1 expressed in endothelial cells is activated downstream of TNF-α, which is not a G protein-coupled receptor agonist. Our data identify P-Rex1 as a critical mediator of vascular barrier disruption. Targeting P-Rex1 may effectively protect against TNF-α- and lipopolysaccharide-induced endothelial junction disruption and vascular hyperpermeability.

Hydrogen Sulfide Attenuates Particulate Matter–Induced Human Lung Endothelial Barrier Disruption via Combined Reactive Oxygen Species Scavenging and Akt Activation

Exposure to particulate air pollution is associated with increased cardiopulmonary morbidity and mortality, although the pathogenic mechanisms are poorly understood. We previously demonstrated that particulate matter (PM) exposure triggers massive oxidative stress in vascular endothelial cells (ECs), resulting in the loss of EC integrity and lung vascular hyperpermeability. We investigated the protective role of hydrogen sulfide (H(2)S), an endogenous gaseous molecule present in the circulation, on PM-induced human lung EC barrier disruption and pulmonary inflammation. Alterations in EC monolayer permeability, as reflected by transendothelial electrical resistance (TER), the generation of reactive oxygen species (ROS), and murine pulmonary inflammatory responses, were studied after exposures to PM and NaSH, an H(2)S donor. Similar to N-acetyl cysteine (5 mM), NaSH (10 μM) significantly scavenged PM-induced EC ROS and inhibited the oxidative activation of p38 mitogen-activated protein kinase. Concurrent with these events, NaSH (10 μM) activated Akt, which helps maintain endothelial integrity. Both of these pathways contribute to the protective effect of H(2)S against PM-induced endothelial barrier dysfunction. Furthermore, NaSH (20 mg/kg) reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in a murine model of PM-induced lung inflammation. These data suggest a potentially protective role for H(2)S in PM-induced inflammatory lung injury and vascular hyperpermeability.

Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors

Recently a new concept has emerged implicating thrombin signaling as the "bridge" that connects tissue damage to hemostatic and inflammatory responses. In view of this concept, we hypothesized that induction of protease-activated receptor (PAR) expression may play a critical role in endotoxin-induced tissue injury through the cellular actions of thrombin. Thus, in this study, temporal changes in expression of key precoagulant molecules, including PARs, in lungs from rabbits rendered endotoxemic by 100 microg/kg lipopolysaccharide (LPS) were examined with measurements of variables reflecting acute lung injury (ALI). ALI induction by LPS was confirmed by blood gas derangement, lung vascular hyperpermeability, and histopathological changes, and was characterized by the deposition of fibrin in the alveolar spaces, bronchioles and vessels. Plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) were highly expressed in lungs after LPS injection. While the peaks in levels of PAI-1 and TF were comparable (12 approximately 13-fold from control), their expression time-courses were different: PAI-1 exhibited a bell-shaped expression pattern and peak at 6 h, whereas TF level reached maximum at 10 h. Of note, LPS induced a rapid and significant increase in levels of PAR-1 compared to control, with a peak level at 1 h (3.3-fold). Although declining thereafter, it remained significantly higher than the control level throughout the study period. Expressions of PAR-2, -3, and -4 were also increased by LPS with different time courses from PAR-1 expression. Immunofluorescence staining for PAR-1 were localized in blood vessels, bronchial epithelium, and alveolar pneumocytes after LPS. These results suggest that the increased expression levels of PARs, in addition to PAI-1 and TF, may, in part, underlie the development of ALI occurring during endotoxemia.

Adult Respiratory Distress Syndrome (ARDS)

The pathophysiology of the adult respiratory distress syndrome (ARDS) seems to be based on a cybernetic imbalance of the central nervous system (CNS), with activation of secondary peripheral effectors (PE). Lung vascular hyperpermeability is a crucial feature of PE actions in ARDS. Kinins (Bk), as PE, are important vascular hyperpermeability-inducing factors, with potential participation in ARDS induction. To test this hypothesis, we produced experimental ARDS in male Wistar rats using the anterior hypothalamic nuclei lesion model. Adrenalectomy, adrenal demedullation and denervation, alpha-adrenergic blockade, and catecholamine (CA) depletion reduced ARDS severity whereas beta-adrenergic blocking and CA uptake I inhibition resulted in a potentiated aspect. The Bk depletion or inhibition of the generation of these peptides resulted in attenuation of the pathologic features of ARDS. Bk half-life prolongation produced intense potentiation of the respiratory syndrome. This work suggests that Bk and CA systems are interactive and interdependent in their pathogenic actions on lungs in ARDS, involving, probably, a reciprocally-activating mechanism.