Showing papers in "American Journal of Physiology-lung Cellular and Molecular Physiology in 2006"
TL;DR: The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks and NF-κB activation is a central event leading to the activation of these networks.
Abstract: The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-κB activation is a central event leading to the activation of these networks. The rol...
674 citations
TL;DR: Two classes of novel, potent small molecules identified from screening compound libraries that restore the function of DeltaF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients are described.
Abstract: Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl− channel. The most common mutation results in a deletion of phenylalanine at position...
523 citations
TL;DR: Cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages and inhibition of IKK ablated the CSE-mediatedIL-8 release.
Abstract: Cigarette smoke-mediated oxidative stress induces an inflammatory response in the lungs by stimulating the release of proinflammatory cytokines. Chromatin remodeling due to histone acetylation and deacetylation is known to play an important role in transcriptional regulation of proinflammatory genes. The aim of this study was to investigate the molecular mechanism(s) of inflammatory responses caused by cigarette smoke extract (CSE) in the human macrophage-like cell line MonoMac6 and whether the treatment of these cells with the antioxidant glutathione (GSH) monoethyl ester, or modulation of the thioredoxin redox system, can attenuate cigarette smoke-mediated IL-8 release. Exposure of MonoMac6 cells to CSE (1% and 2.5%) increased IL-8 and TNF-alpha production vs. control at 24 h and was associated with significant depletion of GSH levels associated with increased reactive oxygen species release in addition to activation of NF-kappaB. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on the NF-kappaB pathway. CSE also reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation. Pretreatment of cells with GSH monoethyl ester, but not thioredoxin/thioredoxin reductase, reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release. Thus cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages. Moreover, cigarette smoke-mediated proinflammatory events are regulated by the redox status of the cells.
476 citations
TL;DR: A comprehensive overview of the rapidly expanding literature on VEGF is provided, finding increasing evidence that this protein plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema.
Abstract: Vascular endothelial growth factor (VEGF) is a pluripotent growth and permeability factor that has a broad impact on endothelial cell function. The lung tissue is very rich in this protein; many different lung cells produce VEGF and also respond to VEGF. VEGF is critical for the development of the lung and serves as a maintenance factor during adult life. In addition to the physiological functions of this protein, there is increasing evidence that VEGF also plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema. Here we provide a comprehensive overview of the rapidly expanding literature.
396 citations
TL;DR: The consequences of TGF-β1 stimulation in pulmonary hypertension are studied to assess its effect on the pulmonary circulation and provide clues about its role in disease progression.
Abstract: Transforming growth factor-β1 (TGF-β1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-β1 stimul...
373 citations
TL;DR: A pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH is demonstrated, demonstrating that reactive oxygen species (ROS) may be involved in both processes.
Abstract: Chronic exposure to low-O2 tension induces pulmonary arterial hypertension (PAH), which is characterized by vascular remodeling and enhanced vasoreactivity. Recent evidence suggests that reactive oxygen species (ROS) may be involved in both processes. In this study, we critically examine the role superoxide and NADPH oxidase plays in the development of chronic hypoxic PAH. Chronic hypoxia (CH; 10% O2 for 3 wk) caused a significant increase in superoxide production in intrapulmonary arteries (IPA) of wild-type (WT) mice as measured by lucigenin-enhanced chemiluminescence. The CH-induced increase in the generation of ROS was obliterated in NADPH oxidase (gp91phox) knockout (KO) mice, suggesting that NADPH oxidase was the major source of ROS. Importantly, pathological changes associated with CH-induced PAH (mean right ventricular pressure, medial wall thickening of small pulmonary arteries, and right heart hypertrophy) were completely abolished in NADPH oxidase (gp91phox) KO mice. CH potentiated vasoconstrictor responses of isolated IPAs to both 5-hydroxytryptamine (5-HT) and the thromboxane mimetic U-46619. Administration of CuZn superoxide dismutase to isolated IPA significantly reduced CH-enhanced superoxide levels and reduced the CH-enhanced vasoconstriction to 5-HT and U-46619. Additionally, CH-enhanced superoxide production and vasoconstrictor activity seen in WT IPAs were markedly reduced in IPAs isolated from NADPH oxidase (gp91phox) KO mice. These results demonstrate a pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH.
282 citations
TL;DR: For the first time, results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta and may play important roles in the regulation of pulmonary and systemic circulation.
Abstract: Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel s...
268 citations
TL;DR: The response pattern observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
Abstract: Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
218 citations
TL;DR: The results indicate that full expression of Hif-1 is essential for hypoxic induction of NHE1 expression and changes in PASMC pH homeostasis and suggest a novel mechanism by which HIF-1 mediates pulmonary vascular remodeling during the pathogenesis of hypoxic pulmonary hypertension.
Abstract: Vascular remodeling resulting from altered pulmonary arterial smooth muscle cell (PASMC) growth is a contributing factor to the pathogenesis of hypoxic pulmonary hypertension. PASMC growth requires...
194 citations
TL;DR: The effect of inhibition of H(2)S formation and administration of NaHS suggests that H( 2)S plays a proinflammatory role in regulating the severity of sepsis and associated organ injury.
Abstract: Endogenous hydrogen sulfide (H2S) is naturally synthesized in various types of mammalian cells from l-cysteine in a reaction catalyzed by two enzymes, cystathionine-γ-lyase (CSE) and/or cystathioni...
194 citations
TL;DR: It is demonstrated that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspases -9 and -9 in a Fas/FasL-independent pathway.
Abstract: Epithelial cells are considered to be a main target of bleomycin-induced lung injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro bleomycin-induced apoptosis in a mouse lung epithelial (MLE) cell line. Bleomycin caused an increase of reactive oxygen species (ROS) resulting in oxidative stress, mitochondrial leakage, and apoptosis. These were associated with elevated caspase-8 and resultant caspase-9 activity and with upregulation of Fas expression. Glutathione and inhibitors of caspase-8 or caspase-9, but not of FasL, inhibited these effects, suggesting their dependence on ROS, caspase-8 and -9, in a Fas/FasL-independent pathway. However, postbleomycin-exposed MLE cells were more sensitive to Fas-mediated apoptosis. These results demonstrate that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspase-9. Fas represents an amplification mechanism, and not a direct trigger of bleomycin-induced epithelial cell apoptosis.
TL;DR: The combined data suggest that TNF-alpha regulates the pulmonary vascular endothelial paracellular pathway, in part, through fyn activation.
Abstract: Tumor necrosis factor (TNF)-α is a key mediator of sepsis-associated multiorgan failure, including the acute respiratory distress syndrome. We examined the role of protein tyrosine phosphorylation ...
TL;DR: It is concluded that alveolar macrophages are an essential player in the initiation of acute lung I/R injury and are a major producer/initiator of TNF-alpha, MCP-1, and MIP-2.
Abstract: Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribu...
TL;DR: A number of cell-specific, pathway- specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases are suggested.
Abstract: Inducible cyclooxygenase (COX-2) and its metabolites have diverse and potent biological actions that are important for both physiological and disease states of lung. The wide variety of prostaglandin (PG) products are influenced by the level of cellular activation, the exact nature of the stimulus, and the specific cell type involved in their production. In turn, the anti- and proinflammatory response of PG is mediated by a blend of specific surface and intracellular receptors that mediate diverse cellular events. The complexity of this system is being at least partially resolved by the generation of specific molecular biological research tools that include cloning and characterization of the enzymes distal to COX-2 and the corresponding receptors to the final cellular products of arachidonic metabolism. The most informative of these approaches have employed genetically modified animals and specific receptor antagonists to determine the exact role of specific COX-2-derived metabolites on specific cell types of the lung in the context of inflammatory models. These data have suggested a number of cell-specific, pathway-specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases.
TL;DR: Caveolae and caveolin-1 coordinate PDGF receptor signaling, leading to myocyte proliferation, and inhibit constitutive activity of p42/p44 MAPK to sustain cell quiescence, which suggests a dynamic relationship in which mitogen stimulation actively reverses caveolae suppression of p 42/p 44 MAPK signal transduction.
Abstract: Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperresponsiveness. Increased muscle mass is du...
TL;DR: It is demonstrated that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolars play an important role in the initial pathogenesis of VILI.
Abstract: In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HV(T)) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HV(T) (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HV(T) (P < 0.05). BAL fluid from rats exposed to 20 min of HV(T) increased nitric oxide synthase activity nearly threefold in naive primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naive macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.
TL;DR: It is concluded that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
Abstract: Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat mode...
TL;DR: Animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses, which may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury, sepsis, acute lung injury, and multiple organ dysfunction syndrome.
Abstract: Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.
TL;DR: A critical role is shown for the GEF-H1 in the Rho activation caused by MT disassembly and GEF/GTP exchange factor is suggested as a key molecule involved in cross talk between MT and actin cytoskeleton in agonist-induced Rho-dependent EC barrier regulation.
Abstract: Endothelial cell (EC) permeability is precisely controlled by cytoskeletal elements [actin filaments, microtubules (MT), intermediate filaments] and cell contact protein complexes (focal adhesions, adherens junctions, tight junctions). We have recently shown that the edemagenic agonist thrombin caused partial MT disassembly, which was linked to activation of small GTPase Rho, Rho-mediated actin remodeling, cell contraction, and dysfunction of lung EC barrier. GEF-H1 is an MT-associated Rho-specific guanosine nucleotide (GDP/GTP) exchange factor, which in MT-unbound state stimulates Rho activity. In this study we tested hypothesis that GEF-H1 may be a key molecule involved in Rho activation, myosin light chain phosphorylation, actin remodeling, and EC barrier dysfunction associated with partial MT disassembly. Our results show that depletion of GEF-H1 or expression of dominant negative GEF-H1 mutant significantly attenuated permeability increase, actin stress fiber formation, and increased MLC and MYPT1 phosphorylation induced by thrombin or MT-depolymerizing agent nocodazole. In contrast, expression of wild-type or activated GEF-H1 mutants dramatically enhanced thrombin and nocodazole effects on stress fiber formation and cell retraction. These results show a critical role for the GEF-H1 in the Rho activation caused by MT disassembly and suggest GEF-H1 as a key molecule involved in cross talk between MT and actin cytoskeleton in agonist-induced Rho-dependent EC barrier regulation.
TL;DR: Real time RT-PCR demonstrated CFTR transcript expression in human AT II cells at a level similar to that in airway epithelial cells and may contribute to cAMP-regulated apical-basolateral fluid transport.
Abstract: Previous studies in intact lung suggest that CFTR may play a role in cAMP-regulated fluid transport from the distal air spaces of the lung. However, the potential contribution of different epitheli...
TL;DR: The data demonstrate that the development of pulmonary hypertension in Shunt lambs is associated with increases in oxidative stress that are not explained by decreases in antioxidant expression or activity.
Abstract: Although oxidative stress is known to contribute to endothelial dysfunction-associated systemic vascular disorders, its role in pulmonary vascular disorders is less clear. Our previous studies, usi...
TL;DR: Results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.
Abstract: Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR-II) and dysfunction of BMPR-II have been implicated in patients with primary pulmonary hypertension (PH). To clar...
TL;DR: The data suggest that perinatal hyperoxia adversely affects alveolar development by disrupting the proper timing of type II cell proliferation and differentiation into type I cells.
Abstract: Type II epithelial cells are essential for lung development and remodeling, as they are precursors for type I cells and can produce vascular mitogens. Although type II cell proliferation takes plac...
TL;DR: Obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O(3), and differences between ob/ob mice and db/db mice, which lack leptin, suggest leptin, acting through Ob-R(a), can modify some pulmonary responsesTo investigate the role of leptin in asthma, obese mice are exposed to air or O( 3) for 3 h.
Abstract: Epidemiological studies indicate the incidence of asthma is increased in obese and overweight humans. Responses to ozone (O3), an asthma trigger, are increased in obese (ob/ob) mice lacking the sat...
TL;DR: It is suggested that macrolide antibiotics can differentially modulate proinflammatory cytokine secretion in NHBE cells, in part through ERK.
Abstract: Macrolide antibiotics decrease proinflammatory cytokine production in airway cells from subjects with chronic airway inflammation. However, in subjects with chronic obstructive pulmonary disease, s...
TL;DR: The results demonstrate the essential requirement of caveolin-1 in mediating the formation of caveolae in endothelial cells in vivo and in negatively regulating IEJ permeability.
Abstract: Caveolin-1, the principal integral membrane protein of caveolae, has been implicated in regulating the structural integrity of caveolae, vesicular trafficking, and signal transduction. Although the...
TL;DR: It is concluded that ICAM-1 and L FA-1 play critical roles in the recruitment of neutrophils into the alveolar space in aerosolized LPS-induced lung inflammation, and LFA-1 serves as a ligand of ICam-1 in the lung.
Abstract: Neutrophil recruitment into lung constitutes a major response to airborne endotoxins. In many tissues endothelial intercellular adhesion molecule-1 (ICAM-1) interacts with lymphocyte function associated antigen-1 (LFA-1) on neutrophils, and this interaction plays a critical role in neutrophil recruitment. There are conflicting reports about the role of ICAM-1 in neutrophil recruitment into lungs. We studied neutrophil recruitment into alveolar space in a murine model of aerosolized LPS-induced lung inflammation. LPS induces at least a 100-fold increase in neutrophil numbers in alveolar space, as determined by flow cytometry of bronchoalveolar lavage fluid. Neutrophil recruitment was reduced by 54% in ICAM-1 null mice and by 45% in LFA-1 null mice. In wild-type mice treated with anti-ICAM-1 and anti-LFA-1 antibodies, there was 51 and 58% reduction in the neutrophil recruitment, respectively. In chimeric mice, generated by the transplantation of mixtures of bone marrows from LFA-1 null and wild-type mice, the normalized recruitment of LFA-1 null neutrophils was reduced by 60% compared with wild-type neutrophils. Neither the treatment of ICAM-1 null mice with a function-blocking antibody to LFA-1 nor the treatment of LFA-1 null mice with anti-ICAM-1 antibody resulted in further reduction in the recruitment compared with untreated ICAM-1 null and LFA-1 null mice. We conclude that ICAM-1 and LFA-1 play critical roles in the recruitment of neutrophils into the alveolar space in aerosolized LPS-induced lung inflammation, and LFA-1 serves as a ligand of ICAM-1 in the lung.
TL;DR: The studies suggest that iron mobilization by alveolar macrophages can be affected by iron and LPS via several pathways, including HAMP-mediated degradation of FPN1, and that these cells may use unique regulatory mechanisms to cope with iron imbalance in the lung.
Abstract: Alveolar macrophages express many proteins important in iron homeostasis, including the iron importer divalent metal transport 1 (DMT1) and the iron exporter ferroportin 1 (FPN1) that likely partic...
TL;DR: It is hypothesized that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal will reduce the inflammation and ALI observed in mice following hemorrhage and subsequent sepsis (CLP) in the authors' murine model of ALI.
Abstract: Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory...
TL;DR: It is demonstrated that MICA/B and ULBP 1, 2, 3, and 4 expression is rare or absent on the cell surface of unstimulated normal human bronchial epithelial cells although transcripts and intracellular proteins are present.
Abstract: Immune surveillance of the airways is critical to maintain the integrity and health of the lung. We have identified a family of ligands expressed on the surface of stressed airway epithelial cells ...