Inhibition of the Lipoxin A4 and Resolvin D1 Receptor Impairs Host Response to Acute Lung Injury Caused by Pneumococcal Pneumonia in Mice

2021 ◽  
Author(s):  
Emily R. Siegel ◽  
Roxanne H Croze ◽  
Xiaohui Fang ◽  
Michael A. Matthay ◽  
Jeffrey Earl Gotts
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Pneumococcal Pneumonia ◽  
Alveolar Epithelium ◽  
D1 Receptor ◽  
Host Responses ◽  
Protein Accumulation ◽  
Resolvin D1 ◽  
Lipoxin A4 ◽  
Injured Lung

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized pro-resolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae, the role of Lipoxin A4 (LXA4) and Resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of ALX/FPR2, the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of pro-inflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.

The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats

2012 ◽  
Vol 303 (3) ◽  
pp. L259-L271 ◽  
Author(s):  
Hans G. Folkesson ◽  
Stephanie R. Kuzenko ◽  
David A. Lipson ◽  
Michael A. Matthay ◽  
Mark A. Simmons
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Fluid Transport ◽  
Unmet Need ◽  
Alveolar Epithelium ◽  
Experimental Models ◽  
Adrenergic Stimulation ◽  
Edema Formation ◽  
Beneficial Effects

There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveolar and pulmonary edema is active vectorial Na+ and Cl− transport across the alveolar epithelium. Several studies have suggested a role for adenosine receptors in regulating this fluid transport in the lung. Furthermore, these studies point to the A2A subtype of adenosine receptor (A2AR) as playing a role to enhance fluid transport, suggesting that activation of the A2AR may enhance alveolar fluid clearance (AFC). The current studies test the potential therapeutic value of the A2AR agonist GW328267C to accelerate resolution of alveolar edema and ALI/ARDS in rats. GW328267C, at concentrations of 10−5 M to 10−3 M, instilled into the airspaces, increased AFC in control animals. GW328267C did not increase AFC beyond that produced by maximal β-adrenergic stimulation. The effect of GW328267C was inhibited by amiloride but was not affected by cystic fibrosis transmembrane conductance regulator inhibition. The drug was tested in three models of ALI, HCl instillation 1 h, LPS instillation 16 h, and live Escherichia coli instillation 2 h before GW328267C instillation. After either type of injury, GW328267C (10−4 M) decreased pulmonary edema formation and restored AFC, measured 1 h after GW328267C instillation. These findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI.

scholarly journals Pathogenesis of Pneumococcal Pneumonia in Cyclophosphamide-Induced Leukopenia in Mice

2002 ◽  
Vol 70 (8) ◽  
pp. 4226-4238 ◽  
Author(s):  
Erjian Wang ◽  
Marie Simard ◽  
Nathalie Ouellet ◽  
Yves Bergeron ◽  
Denis Beauchamp ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pneumococcal Pneumonia ◽  
Diffuse Alveolar Damage ◽  
Interleukin 1 ◽  
Alveolar Epithelium ◽  
Inflammatory Protein ◽  
Transmission Electron ◽  
Pulmonary Capillary ◽  
Alveolar Collapse ◽  
Chemotactic Protein

ABSTRACT Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.

Increased leukotriene C4 in ethchlorvynol-induced acute lung injury in dogs

1987 ◽  
Vol 62 (2) ◽  
pp. 732-738 ◽  
Author(s):  
A. H. Stephenson ◽  
R. S. Sprague ◽  
T. E. Dahms ◽  
A. J. Lonigro
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Leukotriene C4 ◽  
Lung Water ◽  
Control Value ◽  
Edema Fluid ◽  
Injured Lung ◽  
Anesthetized Dogs ◽  
Arterial Plasma

We investigated whether ethchlorvynol (ECV)-induced acute lung injury (ALI) is associated with an increase in leukotriene C4 (LTC4) production. In six pentobarbital sodium-anesthetized dogs, ECV (15 mg/kg iv) introduced into the pulmonary circulation resulted in a 164 +/- 31% increase in extravascular lung water 120 min after ECV administration. Concomitantly, the mean (+/- SE) concentration of LTC4 in arterial plasma measured by radioimmunoassay following 80% EtOH precipitation, XAD-7 extraction and high-pressure liquid chromatography purification was 5.0 +/- 1.3 pg/ml, unchanged from control (pre-ECV) values. In contrast, in pulmonary edema fluid 120 min post-ECV, the LTC4 concentration was 35.2 +/- 10.8 pg/ml, sevenfold greater than those values found in the arterial plasma (P less than 0.01). In six additional dogs, 120 min after unilateral ALI had been induced with ECV (9 mg/kg iv), LTC4 in the bronchoalveolar lavage (BAL) of the uninjured lung was 12.1 +/- 1.5 pg/ml, unchanged from pre-ECV values, whereas, LTC4 in the BAL of the injured lung increased from a control value of 10.2 +/- 1.6 to 24.2 +/- 3.5 pg/ml (P less than 0.01) 120 min after ECV administration. These results demonstrate that, in ECV-induced acute lung injury, LTC4 concentrations in pulmonary edema fluid are considerably greater than those found in arterial plasma in the case of bilateral acute lung injury and significantly greater in the BAL of the injured lung compared with the uninjured lung in the case of unilateral acute lung injury. The results are a necessary first step in support of the hypothesis that leukotrienes participate in the altered permeability of ECV-induced acute lung injury.

scholarly journals Resolvin D1 and Lipoxin A4 Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e98773 ◽  
Author(s):  
Camilia R. Martin ◽  
Munir M. Zaman ◽  
Calvin Gilkey ◽  
Maria V. Salguero ◽  
Hatice Hasturk ◽  
...  
Keyword(s):  
Lung Injury ◽  
Wall Thickness ◽  
Murine Model ◽  
Resolvin D1 ◽  
Lipoxin A4 ◽  
Septal Wall ◽  
Septal Wall Thickness

Overexpression of the Na-K-ATPase α2-subunit improves lung liquid clearance during ventilation-induced lung injury

2008 ◽  
Vol 294 (6) ◽  
pp. L1233-L1237 ◽  
Author(s):  
Yochai Adir ◽  
Lynn C. Welch ◽  
Vidas Dumasius ◽  
Phillip Factor ◽  
Jacob I. Sznajder ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Basolateral Membrane ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial ◽  
Rat Lungs ◽  
Injured Lung ◽  
Normal Rat ◽  
Lung Liquid ◽  
Ventilation Induced Lung Injury

Mechanical ventilation with high tidal volumes (HVT) impairs lung liquid clearance (LLC) and downregulates alveolar epithelial Na-K-ATPase. We have previously reported that the Na-K-ATPase α2-subunit contributes to LLC in normal rat lungs. Here we tested whether overexpression of Na-K-ATPase α2-subunit in the alveolar epithelium would increase clearance in a HVT model of lung injury. We infected rat lungs with a replication-incompetent adenovirus that expresses Na-K-ATPase α2-subunit gene (Adα2) 7 days before HVT mechanical ventilation. HVT ventilation decreased LLC by ∼50% in untreated, sham, and Adnull-infected rats. Overexpression of Na-K-ATPase α2-subunit prevented the decrease in clearance caused by HVT and was associated with significant increases in Na-K-ATPase α2 protein abundance and activity in peripheral lung basolateral membrane fractions. Ouabain at 10−5 M, a concentration that inhibits the α2 but not the Na-K-ATPase α1, decreased LLC in Adα2-infected rats to the same level as sham and Adnull-infected lungs, suggesting that the increased clearance in Adα2 lungs was due to Na-K-ATPase α2 expression and activity. In summary, we provide evidence that augmentation of the Na-K-ATPase α2-subunit, via gene transfer, may accelerate LLC in the injured lung.

Neutralizing the complement component C5a protects against lung injury and extrapulmonary organ injury in pneumococcal pneumonia induced sepsis

Pneumologie ◽  
2014 ◽  
Vol 68 (S 01) ◽  
Author(s):  
H Müller-Redetzky ◽  
U Henke-Kellermann ◽  
T Tschernig ◽  
S Wienhold ◽  
M Polikarpova ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pneumococcal Pneumonia ◽  
Complement Component ◽  
Organ Injury

scholarly journals Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury

2021 ◽  
Author(s):  
Yuanxu Jiang ◽  
Mingzhu Xia ◽  
Jing Xu ◽  
Qiang Huang ◽  
Zhongliang Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Pulmonary Edema ◽  
Cell Injury ◽  
A549 Cells ◽  
Alveolar Epithelial ◽  
Phosphorylated Akt ◽  
Epithelial Sodium Channel Enac

AbstractDexmedetomidine (Dex), a highly selective α2-adrenergic receptor (α2AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, β-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1β, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, β-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

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