Vimentin regulates activation of the NLRP3 inflammasome.

Activation of the NLRP3 inflammasome and subsequent maturation of IL-1β have been implicated in acute lung injury (ALI), resulting in inflammation and fibrosis. We investigated the role of vimentin, a type III intermediate filament, in this process using three well-characterized murine models of ALI known to require NLRP3 inflammasome activation. We demonstrate that central pathophysiologic events in ALI (inflammation, IL-1β levels, endothelial and alveolar epithelial barrier permeability, remodelling and fibrosis) are attenuated in the lungs of Vim(-/-) mice challenged with LPS, bleomycin and asbestos.

β₂-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis.

Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6.

PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice.

Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema.

Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ.

Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation.

The effect of rosuvastatin in a murine model of influenza A infection.

Rationale: HMG-CoA reductase inhibitors such as rosuvastatin may have immunomodulatory and anti-inflammatory effects that may reduce the severity of influenza A infection. We hypothesized that rosuvastatin would decrease viral replication, attenuate lung injury, and improve mortality following influenza A infection in mice.

Methods: C57Bl/6 mice were treated daily with rosuvastatin (10 mg/kg/day) supplemented in chow (or control chow) beginning three days prior to infection with either A//Udorn/72 [H3N2] or A/WSN/33 [H1N1] influenza A virus (1×10(5) pfu/mouse).

Particulate matter Air Pollution induces hypermethylation of the p16 promoter Via a mitochondrial ROS-JNK-DNMT1 pathway.

Exposure of human populations to chronically elevated levels of ambient particulate matter air pollution < 2.5 μm in diameter (PM(2.5)) has been associated with an increase in lung cancer incidence.

Alcohol worsens acute lung injury by inhibiting alveolar sodium transport through the adenosine A1 receptor.

Objective: Alcohol intake increases the risk of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) and is associated with poor outcomes in patients who develop these syndromes. No specific therapies are currently available to treat or decrease the risk of ARDS in patients with alcoholism. We have recently shown increased levels of lung adenosine inhibit alveolar fluid clearance, an important predictor of outcome in patients with ARDS.

Minimizing oxidation and stable nanoscale dispersion improves the biocompatibility of graphene in the lung.

To facilitate the proposed use of graphene and its derivative graphene oxide (GO) in widespread applications, we explored strategies that improve the biocompatibility of graphene nanomaterials in the lung. In particular, solutions of aggregated graphene, Pluronic dispersed graphene, and GO were administered directly into the lungs of mice. The introduction of GO resulted in severe and persistent lung injury.

Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β(1) signalling.

Background: The development of organ fibrosis after injury requires activation of transforming growth factor β(1) which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β(1)-mediated transcription.

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury.

Laminins are heterotrimeric glycoproteins of the extracellular matrix that are secreted by epithelial cells and which are crucial for the normal structure and function of the basement membrane. We have generated a mouse harboring a conditional knockout of α3 laminin (Lama3(fl/fl)), one of the main laminin subunits in the lung basement membrane. At 60 days after intratracheal treatment of adult Lama3(fl/fl) mice with an adenovirus encoding Cre recombinase (Ad-Cre), the protein abundance of α3 laminin in whole lung homogenates was more than 50% lower than that in control-treated mice, suggesting a relatively long half-life for the protein in the lung.

Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice.

Background: Exposure to particulate matter (PM) air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI) tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles.

Methods: We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant.

Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms.

Background: Exposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism.

Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ.

Rationale: Diabetic patients have a lower incidence of acute respiratory distress syndrome (ARDS), and those who develop ARDS are less likely to die. The mechanisms that underlie this protection are unknown.

Objectives: To determine whether leptin resistance, a feature of diabetes, prevents fibroproliferation after lung injury.

Epithelial cell death is an important contributor to oxidant-mediated acute lung injury.

Rationale: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown.

Objectives: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury.

[Vasoconstriction is required for edema of contralateral lung after reperfusion injury of one lung].

Ischemia-reperfusion (IR) lung injury is a significant cause of morbidity and mortality in certain clinical scenarios that include transplantation, thromboendarterectomy and reexpansion injury of the lung. Edema of the contralateral lung after IR injury of one lung has been reported and this study was aimed to clarify the pathophysiology of this phenomenon. One-lung ischemia/hypoxia followed by reperfusion with either blood or an acellular plasma substitute was achieved in an isolated rabbit lung model by hilum clamping.

Biocompatible nanoscale dispersion of single-walled carbon nanotubes minimizes in vivo pulmonary toxicity.

Excitement surrounding the attractive physical and chemical characteristics of single walled carbon nanotubes (SWCNTs) has been tempered by concerns regarding their potential health risks. Here we consider the lung toxicity of nanoscale dispersed SWCNTs (mean diameter approximately 1 nm). Because dispersion of the SWCNTs increases their aspect ratio relative to as-produced aggregates, we directly test the prevailing hypothesis that lung toxicity associated with SWCNTs compared with other carbon structures is attributable to the large aspect ratio of the individual particles.

Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation.

Elevated ambient levels of particulate matter air pollution are associated with excess daily mortality, largely attributable to increased rates of cardiovascular events. We have previously reported that particulate matter induces p53-dependent apoptosis in primary human alveolar epithelial cells. Activation of the intrinsic apoptotic pathway by p53 often requires the transcription of the proapoptotic Bcl-2 proteins Noxa, Puma, or both.

Mitochondrial complex III-generated oxidants activate ASK1 and JNK to induce alveolar epithelial cell death following exposure to particulate matter air pollution.

We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA (rho0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM2.

[Effect of hypocapnia/alkalosis on the fluid filtration rate in isolated and perfused rabbit lungs].

Hypocapnia/alkalosis is a consequence of several lung and metabolic pathologies. The aim of this study was to determine whether the increase of fluid filtration rate (FFR) that occurs during Hypocapnia/alkalosis circumstances is determined by hypocapnia, alkalosis or both. 7 groups were formed (N=36) using isolated rabbit lungs.

Stretch-induced activation of AMP kinase in the lung requires dystroglycan.

Lung cells are exposed to cyclic stretch during normal respiration and during positive pressure mechanical ventilation administered to support gas exchange. Dystroglycan is a ubiquitously expressed matrix receptor that is required for normal basement membrane formation during embryogenesis and for maintaining the function of skeletal muscle myocytes and neurons where it links cells to matrix. We previously reported that equibiaxial stretch of primary alveolar epithelial cells activated the MAP kinase pathway ERK1/2 through a mechanism that required an interaction between dystroglycan and matrix.

Beneficial effects of hydrocortisone and papaverine on a model of pulmonary embolism induced by autologous blood clots in isolated and perfused rabbit lungs.

Background And Objective: Mechanical obstruction has been considered the prime determinant of haemodynamic changes after pulmonary embolism (PE); however, the function of vasoconstrictive and inflammatory mediators in the physiopathology of this disease is unclear. The aim of this investigation was to study the effect of an anti-inflammatory and a vasodilator in a setting of induced PE.

Methods: A prospective, laboratory study was undertaken using 30 New Zealand white rabbits.

The intrinsic apoptotic pathway is required for lipopolysaccharide-induced lung endothelial cell death.

LPS has been implicated in the pathogenesis of endothelial cell death associated with Gram-negative bacterial sepsis. The binding of LPS to the TLR-4 on the surface of endothelial cells initiates the formation of a death-inducing signaling complex at the cell surface. The subsequent signaling pathways that result in apoptotic cell death remain unclear and may differ among endothelial cells in different organs.

Electroporation-mediated gene transfer of the Na+,K+ -ATPase rescues endotoxin-induced lung injury.

Rationale: Acute lung injury and acute respiratory distress syndrome are common clinical syndromes resulting largely from the accumulation of and inability to clear pulmonary edema, due to injury to the alveolar epithelium. Gene therapy may represent an important alternative for the treatment and prevention of these diseases by restoring alveolar epithelial function. We have recently developed an electroporation strategy to transfer genes to the lungs of mice, with high efficiency and low inflammation.

[Effect of changes in airway pressure and the inspiratory volume on the fluid filtration rate and pulmonary artery pressure in isolated rabbit lungs perfused with blood and acellular solution].

It has been reported that ventilation with large tidal volumes causes pulmonary edema in rats by the stimulation and release of proinflammatory mediators. Our objective was to determine the level at which volutrauma induced by changes in Airway Pressure (PAW) and Inspiratory Volume (VI) produce significant changes on the Fluid Filtration Rate (FFR) and Pulmonary Artery Pressure (PAP) in lungs perfused with blood (cellular groups) or with a buffer-albumin solution (acellular groups), with a Positive End Expiratory Pressure (PEEP) 0 or 2 cmH2O and to study the effect of a vasodilator with antiinflammatory properties (fenoterol) in blood-perfused groups. Three experimental groups were used: the cellular groups studied the effect of increased PAW and IV in isolated lungs perfused with blood and PEEP 0 and 2; the acellular groups studied the increased PAW and IV in isolated lungs perfused with a buffer-albumin solution and PEEP 0 and 2; The fenoterol group studied the effect of increased PAW and IV in isolated lungs perfused with blood + fenoterol and PEEP 2.