Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extravascular coagulation within the lung airspace is a hallmark of respiratory distress syndrome (RDS) in premature infants. We previously showed that covalent antithrombin-heparin complex (ATH) is superior to noncovalent antithrombin (AT) + heparin (H) mixtures at inhibiting plasma thrombin generation on rat fetal distal lung epithelium (FDLE) in vitro. However, heparin cofactor II (HC) has been shown to selectively inhibit thrombin, which may be advantageous if other enzyme activities are present in the airspace. We compared the abilities of ATH, covalent HC-heparin complex (HCH), and covalent HC-dermatan sulfate (HCD) to inhibit thrombin generation on FDLE in plasmas from either adults or newborns. In the presence of ATH, peak free thrombin generation in adult plasma on the cell surface was reduced by 92% compared with controls (no anticoagulant). However, whereas HCH reduced peak free thrombin generation in adult plasma by 81%, HCD was only able to reduce activity by 33%. All covalent complexes caused a greater decrease in thrombin activity compared with that with the corresponding noncovalent serpin + heparinoid mixtures. Experiments in plasma from newborns resulted in peak free thrombin that was less than or equal to that in adult plasma when covalent conjugates were added. Relative peak free thrombin was proportional to rate of prothrombin consumption and amount of thrombin-inhibitor complexes formed. In vivo, experiments in newborn rats showed that a greater percentage of intratracheally instilled ATH and HCH could be recovered in lung lavage fluid compared withwith that for HCD. In summary, ATH, HCH, and HCD are inhibitors of thrombin generation on FDLE superior to the corresponding noncovalent mixtures, with ATH and HCH being more potent than HCD. Covalent conjugates of AT or HC with H may be preferred in treatment of extravascular coagulation.
Am J Respir Cell Mol Biol 2003 Feb
PMID:Effect of covalent serpin-heparinoid complexes on plasma thrombin generation on fetal distal lung epithelium. 1254 Apr 82

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.
Am J Physiol Lung Cell Mol Physiol 2003 May
PMID:High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance. 1256 62

The intracellular serine/threonine kinase protein kinase C (PKC) has an important role in the genesis of pulmonary edema. This review discusses the PKC-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury characteristic of the respiratory distress syndrome. Thus the paradigms of PKC-induced lung injury are discussed within the context of pulmonary transvascular fluid exchange. We focus on the signal transduction pathways that are modulated by PKC and their effect on lung endothelial permeability. Specifically, alpha-thrombin, tumor necrosis factor (TNF)-alpha, and reactive oxygen species are discussed because of their well-established roles in both human and experimental lung injury. We conclude that PKC, most likely PKC-alpha, is a primary supporter for lung endothelial injury in response to alpha-thrombin, TNF-alpha, and reactive oxygen species.
Am J Physiol Lung Cell Mol Physiol 2003 Mar
PMID:Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury. 1257 83

Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.
Am J Respir Cell Mol Biol 2003 Jul
PMID:Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation. 1260 Aug 32

Targeted deletion of the surfactant protein (SP)-B locus in mice causes lethal neonatal respiratory distress. To assess the importance of SP-B for postnatal lung function, compound transgenic mice were generated in which the mouse SP-B cDNA was conditionally expressed under control of exogenous doxycycline in SP-B-/- mice. Doxycycline-regulated expression of SP-B fully corrected lung function in compound SP-B-/- mice and protected mice from respiratory failure at birth. Withdrawal of doxycycline from adult compound SP-B-/- mice resulted in decreased alveolar content of SP-B, causing respiratory failure when SP-B concentration was reduced to <25% of normal levels. Decreased SP-B was associated with low alveolar content of phosphatidylglycerol, accumulation of misprocessed SP-C proprotein in the air spaces, increased protein content in bronchoalveolar lavage fluid, and altered surfactant activity in vitro. Consistent with surfactant dysfunction, hysteresis, maximal tidal volumes, and end expiratory volumes were decreased. Reduction of alveolar SP-B content causes surfactant dysfunction and respiratory failure, indicating that SP-B is required for postnatal lung function.
Am J Physiol Lung Cell Mol Physiol 2003 Sep
PMID:SP-B deficiency causes respiratory failure in adult mice. 1290 17

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality. Enhanced fibrosis and elevated procollagen III levels have been linked to increased mortality. We hypothesized that transforming growth factor (TGF)-beta 1 may play an important role in ARDS, given its role in stimulating fibrosis. Using reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) and immunohistochemistry, we analyzed lung tissue from four fibroproliferative ARDS cases and control subjects. We also compared active TGF-beta 1 levels in the bronchoalveolar lavage (BAL) fluid of 13 de novo ARDS cases, and 7 normal control subjects. RT in situ PCR showed TGF-beta 1 mRNA expression in fibroproliferative ARDS cases. Immunohistochemistry confirmed protein expression in these samples. Controls were negative for both techniques. In the newly enrolled ARDS cases, TGF-beta 1 levels, as measured by luciferase assay, were elevated in the 11 of 13 samples, averaging 98 +/- 40 pg/mg protein. Controls had no detectable TGF-beta 1 activity. These data suggest that activation of TGF-beta 1 may be important in the early phases of acute lung injury in addition to driving fibroproliferation. These data may lead to new therapeutic approaches in ARDS through more targeted inhibition of fibrosis.
Am J Respir Cell Mol Biol 2003 Apr
PMID:The acute respiratory distress syndrome: a role for transforming growth factor-beta 1. 1265 39

Gram-negative bacterial sepsis remains a common, life-threatening event. The prognosis for patients who develop sepsis-related complications, including the development of acute respiratory distress syndrome (ARDS), remains poor. A common finding among patients and experimental animals with sepsis and ARDS is endothelial injury and/or dysfunction. A component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, has been implicated in the pathogenesis of much of the endothelial cell injury and/or dysfunction associated with these disease states. LPS is a highly proinflammatory molecule that elicits a wide array of endothelial responses, including the upregulation of cytokines, adhesion molecules, and tissue factor. In addition to activation, LPS induces endothelial cell death that is apoptotic in nature. This review summarizes the evidence for LPS-induced vascular endothelial injury and examines the molecular signaling pathways that activate and inhibit LPS-induced endothelial apoptosis. Furthermore, the role of apoptotic signaling molecules in mediating LPS-induced activation of endothelial cells will be considered.
Am J Physiol Lung Cell Mol Physiol 2003 Jun
PMID:Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. 1273 86

Stridor in the newborn is not an unusual entity. This article describes a rare presentation of neonatal respiratory distress caused by a benign nasopharyngeal salivary gland analage tumor.
Pediatr Pathol Mol Med
PMID:Case report: congenital salivary gland analage tumor presenting with neonatal respiratory distress. 1274 71

Patients with acute respiratory distress syndrome are at increased risk for developing multiorgan system dysfunction. The goal of this study was to establish an in vivo murine model to assess the differential effects of ventilation-protective strategies on the development of acute lung injury and systemic organ inflammation. C57B/6 mice were randomized to mechanical ventilation (MV) with conventional, high (17 ml/kg) or protective, low (6 ml/kg) tidal volume (VT) after intratracheal hydrochloric acid or no intervention. Mean arterial pressure was continuously monitored during MV and did not differ between groups. After 4 h, lung injury was assessed by measurement of wet/dry lung weight, lung lavage protein concentration and cell count, and histology. Concentration of IL-6, TNF-alpha, VEGF, and VEGF receptor-2 (VEGFR2) was measured in lung, liver, kidney, and heart. Results were compared with control, spontaneously breathing mice. Lung injury and altered pulmonary cytokine expression were not detected after MV of healthy mice with low or high VT. Although MV did not significantly alter IL-6 or TNF-alpha in systemic organs, VEGF concentration significantly increased in liver and kidney. After acid aspiration, mice ventilated with high VT manifested lung injury and increased IL-6 and VEGFR2 in lung, liver, and kidney, whereas VEGF increased only in liver and kidney. MV with low VT after acid aspiration attenuated lung injury, both IL-6 and VEGFR2 expression in lung and systemic organs, and hepatic, but not renal, increased VEGF. Our data suggest that MV strategy has differential effects on systemic inflammatory changes and thus may selectively predispose to systemic organ dysfunction.
Am J Physiol Lung Cell Mol Physiol 2003 Sep
PMID:Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice. 1275 85

Decreased circulating protein C and increased circulating thrombomodulin are markers of the prothrombotic, antifibrinolytic state associated with poor outcomes in sepsis but have not been measured in patients with ALI (acute lung injury)/ARDS (acute respiratory distress syndrome). We measured circulating and intra-alveolar protein C and thrombomodulin in 45 patients with ALI/ARDS from septic and nonseptic causes and correlated the levels with clinical outcomes. Plasma protein C levels were lower in ALI/ARDS compared with normal. Lower levels of protein C were associated with worse clinical outcomes, including death, fewer ventilator-free days, and more nonpulmonary organ failures, even when only patients without sepsis were analyzed. Levels of thrombomodulin in pulmonary edema fluid from ALI/ARDS patients were >10-fold higher than normal plasma and 2-fold higher than ALI/ARDS plasma. Higher edema fluid thrombomodulin levels were associated with worse clinical outcomes. The higher levels in edema fluid compared with plasma suggest local release of soluble thrombomodulin in the lung, possibly from a lung epithelial source. To determine whether lung epithelial cells can release thrombomodulin, A549 cells and primary isolates of human alveolar type II cells were exposed to H2O2 or inflammatory cytokines. Both epithelial cell types released thrombomodulin into the media. In summary, the protein C system is markedly disrupted in patients with ALI/ARDS from both septic and nonseptic causes. The protein C system may be a potential therapeutic target in patients with ALI/ARDS.
Am J Physiol Lung Cell Mol Physiol 2003 Sep
PMID:Protein C and thrombomodulin in human acute lung injury. 1275 94


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