scholarly journals Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier

2018 ◽  
Vol 314 (5) ◽  
pp. L808-L821 ◽  
Author(s):  
Ting Zhou ◽  
Zhihong Yu ◽  
Ming-Yuan Jian ◽  
Israr Ahmad ◽  
Carol Trempus ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Lung Injury ◽  
Cell Monolayer ◽  
Rho Kinase ◽  
Lavage Fluid ◽  
Bronchial Epithelial Cell ◽  
Apical Surface ◽  
Acid Aspiration ◽  
Primary Bronchial Epithelial Cell ◽  
Barrier Resistance

Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO−/−) mice, and CD44 gene-deficient (CD44−/−) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44−/− resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO−/− mice. Isolated perfused lungs of HCl instilled WT but not of CD44−/− mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.

scholarly journals Anti-Inflammatory Effects of Ellagic Acid on Acute Lung Injury Induced by Acid in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Daniely Cornélio Favarin ◽  
Maxelle Martins Teixeira ◽  
Ednéia Lemos de Andrade ◽  
Claudiney de Freitas Alves ◽  
Javier Emilio Lazo Chica ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ellagic Acid ◽  
Neutrophil Migration ◽  
Lavage Fluid ◽  
Positive Control ◽  
Oral Route ◽  
Dexamethasone Treatment ◽  
Acid Aspiration ◽  
Anti Inflammatory

Acute lung injury (ALI) is characterized by alveolar edema and uncontrolled neutrophil migration to the lung, and no specific therapy is still available. Ellagic acid, a compound present in several fruits and medicinal plants, has shown anti-inflammatory activity in several experimental disease models. We used the nonlethal acid aspiration model of ALI in mice to determine whether preventive or therapeutic administration of ellagic acid (10 mg/kg; oral route) could interfere with the development or establishment of ALI inflammation. Dexamethasone (1 mg/kg; subcutaneous route) was used as a positive control. In both preventive and therapeutic treatments, ellagic acid reduced the vascular permeability changes and neutrophil recruitment to the bronchoalveolar lavage fluid (BALF) and to lung compared to the vehicle. In addition, the ellagic acid accelerated the resolution for lung neutrophilia. Moreover, ellagic acid reduced the COX-2-induced exacerbation of inflammation. These results were similar to the dexamethasone. However, while the anti-inflammatory effects of dexamethasone treatment were due to the reduced activation of NF-κB and AP-1, the ellagic acid treatment led to reduced BALF levels of IL-6 and increased levels of IL-10. In addition, dexamethasone treatment reduced IL-1β. Together, these findings identify ellagic acid as a potential therapeutic agent for ALI-associated inflammation.

scholarly journals Synergy between acid and endotoxin in an experimental model of aspiration-related lung injury progression

2015 ◽  
Vol 309 (10) ◽  
pp. L1103-L1111 ◽  
Author(s):  
Konstantin Tetenev ◽  
Mary E. Cloutier ◽  
Jessica A. von Reyn ◽  
Jennifer L. Ather ◽  
James Candon ◽  
...  
Keyword(s):  
Lung Injury ◽  
Injury Severity ◽  
Human Subjects ◽  
Lavage Fluid ◽  
Lung Mechanics ◽  
Acid Aspiration ◽  
Tnf Α ◽  
Experimental Findings ◽  
Risk Of Aspiration ◽  
Injury Progression

Aspiration is a common cause of lung injury, but it is unclear why some cases are self-limited while others progress to acute respiratory distress syndrome (ARDS). Sporadic exposure to more than one insult could account for this variable progression. We investigated whether synergy between airway acid and endotoxin (LPS) amplifies injury severity in mice and whether LPS levels in human patients could corroborate our experimental findings. C57BL/6 mice aspirated acid (pH 1.3) or normal saline (NS), followed by LPS aerosol or nothing. Bronchoalveolar lavage fluid (BALF) was obtained 2 to 49 h later. Mice were injected with FITC-dextran 25 h after aspiration and connected to a ventilator, and lung elastance ( H) measured periodically following deep inflation (DI). Endotracheal and gastric aspirates were also collected from patients in the intensive care unit and assayed for pH and LPS. Lung instability (Δ H following DI) and pressure-volume hysteresis in acid- or LPS-exposed mice was greater than in controls but markedly greater in the combined acid/LPS group. BALF neutrophils, cytokines, protein, and FITC-dextran in the acid/LPS mice were geometrically higher than all other groups. BALF from acid-only mice markedly amplified LPS-induced TNF-α production in cultured macrophages. Human subjects had variable endotracheal LPS levels with the highest burden in those at higher risk of aspiration. Acid aspiration amplifies LPS signaling in mice to disrupt barrier function and lung mechanics in synergy. High variation in airway LPS and greater airway LPS burden in patients at higher risk of aspiration could help explain the sporadic progression of aspiration to ARDS.

scholarly journals Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

2015 ◽  
Vol 308 (9) ◽  
pp. L891-L903 ◽  
Author(s):  
Ahmed Lazrak ◽  
Judy Creighton ◽  
Zhihong Yu ◽  
Svetlana Komarova ◽  
Stephen F. Doran ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Smooth Muscle ◽  
Lung Injury ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Lavage Fluid ◽  
Airway Smooth Muscle Cells ◽  
Intratracheal Administration ◽  
Epithelial Lining Fluid ◽  
Intracellular Ca

Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR.

scholarly journals Functional contribution of CXCR2 to lung injury after aspiration of acid and gastric particulates

2010 ◽  
Vol 298 (3) ◽  
pp. L382-L391 ◽  
Author(s):  
Jean A. Nemzek ◽  
Omorodola Abatan ◽  
Christopher Fry ◽  
Aladdein Mattar
Keyword(s):  
Lung Injury ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Experimental Models ◽  
Neutrophil Recruitment ◽  
Acid Aspiration ◽  
Cellular Aggregation ◽  
Chemokine Receptor Cxcr2 ◽  
Deficient Mice

The effects of individual ELR+ CXC chemokines have been documented in experimental models of acid aspiration. However, aspiration lung injury would be influenced by the combined effects of these chemokines and other factors related to their function. Therefore, the role of the chemokine receptor CXCR2 was examined in lung injury induced by aspiration of acid and acid with gastric particulates. Anesthetized mice were given intratracheal injections of saline, acid solution, or acid containing gastric particles. Within 6 h, bronchoalveolar lavage fluid neutrophils and albumin increased relative to the severity of the insult. Immunohistochemistry and RT-PCR demonstrated striking increases in pulmonary expression of CXCR2 after aspiration. In CXCR2-deficient mice, neutrophil recruitment to airways was significantly reduced after aspiration of either acid or acid with particles. However, lung injury scores were unaffected in Ccr2−/− mice in the acid + particles group. Esterase-stained lung tissue demonstrated that focal aggregates of inflammatory cells contained neutrophils in the Ccr2−/− mice. These studies suggest CXCR2 and its ligands are dominant mediators of neutrophil recruitment to airways after aspiration. However, CXCR2-independent mechanisms recruit neutrophils into areas of cellular aggregation after aspiration of acidified gastric particulates.

scholarly journals Mitigation of chlorine-induced lung injury by low-molecular-weight antioxidants

2008 ◽  
Vol 295 (5) ◽  
pp. L733-L743 ◽  
Author(s):  
Martin Leustik ◽  
Stephen Doran ◽  
Andreas Bracher ◽  
Shawn Williams ◽  
Giuseppe L. Squadrito ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Acidosis ◽  
Lavage Fluid ◽  
Heart Tissue ◽  
Low Molecular Weight ◽  
Sprague Dawley ◽  
Alveolar Epithelial ◽  
High Concentrations

Chlorine (Cl2) is a highly reactive oxidant gas used extensively in a number of industrial processes. Exposure to high concentrations of Cl2 results in acute lung injury that may either resolve spontaneously or progress to acute respiratory failure. Presently, the pathophysiological sequelae associated with Cl2-induced acute lung injury in conscious animals, as well as the cellular and biochemical mechanisms involved, have not been elucidated. We exposed conscious Sprague-Dawley rats to Cl2 gas (184 or 400 ppm) for 30 min in environmental chambers and then returned them to room air. At 1 h after exposure, rats showed evidence of arterial hypoxemia, respiratory acidosis, increased levels of albumin, IgG, and IgM in bronchoalveolar lavage fluid (BALF), increased BALF surfactant surface tension, and significant histological injury to airway and alveolar epithelia. These changes were more pronounced in the 400-ppm-exposed rats. Concomitant decreases of ascorbate (AA) and reduced glutathione (GSH) were also detected in both BALF and lung tissues. In contrast, heart tissue AA and GSH content remained unchanged. These abnormalities persisted 24 h after exposure in rats exposed to 400 ppm Cl2. Rats injected systemically with a mixture of AA, deferoxamine, and N-acetyl-l-cysteine before exposure to 184 ppm Cl2 had normal levels of AA, lower levels of BALF albumin and normal arterial Po2 and Pco2 values. These findings suggest that Cl2 inhalation damages both airway and alveolar epithelial tissues and that resulting effects were ameliorated by prophylactic administration of low-molecular-weight antioxidants.

scholarly journals Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury

2019 ◽  
Vol 20 (7) ◽  
pp. 1678 ◽  
Author(s):  
Yi-Chen Lee ◽  
Chun-Yu Lin ◽  
Yen-Hsu Chen ◽  
Wen-Chin Chiu ◽  
Yen-Yun Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial ◽  
Epithelial Cell Lines ◽  
Nfκb Pathway ◽  
Pro Inflammatory Cytokines

Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-β, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.

scholarly journals Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Asbjørn G. Petersen ◽  
Peter C. Lind ◽  
Anne-Sophie B. Jensen ◽  
Mark A. Eggertsen ◽  
Asger Granfeldt ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Primary Endpoint ◽  
Bronchoalveolar Lavage Fluid ◽  
Distress Syndrome ◽  
Pulmonary Hemorrhage ◽  
Lavage Fluid

Abstract Background Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio. Methods ARDS was induced in female pigs (42–49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h. Results Final senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar–capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid. Conclusions In summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

scholarly journals A role for bronchial epithelial autotaxin in ventilator-induced lung injury

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ioanna Nikitopoulou ◽  
Ioanna Ninou ◽  
Nikolaos Manitsopoulos ◽  
Ioanna Dimopoulou ◽  
Stylianos E. Orfanos ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protein Concentration ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Lavage Fluid ◽  
Bronchial Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Lung Histopathology ◽  
Genetic Deletion

Abstract Background The pathophysiology of acute respiratory distress syndrome (ARDS) may eventually result in heterogeneous lung collapse and edema-flooded airways, predisposing the lung to progressive tissue damage known as ventilator-induced lung injury (VILI). Autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular lysophosphatidic acid (LPA) production, has been suggested to play a pathogenic role in, among others, pulmonary inflammation and fibrosis. Methods C57BL/6 mice were subjected to low and high tidal volume mechanical ventilation using a small animal ventilator: respiratory mechanics were evaluated, and plasma and bronchoalveolar lavage fluid (BALF) samples were obtained. Total protein concentration was determined, and lung histopathology was further performed Results Injurious ventilation resulted in increased BALF levels of ATX. Genetic deletion of ATX from bronchial epithelial cells attenuated VILI-induced pulmonary edema. Conclusion ATX participates in VILI pathogenesis.

scholarly journals Effects of Positive End-expiratory Pressure Titration and Recruitment Maneuver on Lung Inflammation and Hyperinflation in Experimental Acid Aspiration–induced Lung Injury

2012 ◽  
Vol 117 (6) ◽  
pp. 1322-1334 ◽  
Author(s):  
Aline M. Ambrosio ◽  
Rubin Luo ◽  
Denise T. Fantoni ◽  
Claudia Gutierres ◽  
Qin Lu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Recruitment Maneuver ◽  
Alveolar Wall ◽  
Arterial Oxygenation ◽  
Positive End Expiratory Pressure ◽  
Acid Aspiration ◽  
Recruitment Maneuvers ◽  
Alveolar Area

Background In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Methods Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Results Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. Conclusion In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

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