PCTR1 improves pulmonary edema fluid clearance through activating the sodium channel and lymphatic drainage in lipopolysaccharide‐induced ARDS

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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Neuropeptides in pulmonary edema fluid of adult respiratory distress syndrome

Inflammation ◽

10.1007/bf00918976 ◽

1992 ◽

Vol 16 (5) ◽

pp. 509-517 ◽

Cited By ~ 22

Author(s):

Roger F. Espiritu ◽

Jean -Francois Pittet ◽

Michael A. Matthay ◽

Edward J. Goetzl

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Pulmonary Edema ◽

Adult Respiratory Distress Syndrome ◽

Distress Syndrome ◽

Edema Fluid

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Edema Fluid and Coagulation Changes During Fulminant Pulmonary Edema

CHEST Journal ◽

10.1378/chest.79.1.43 ◽

1981 ◽

Vol 79 (1) ◽

pp. 43-49 ◽

Cited By ~ 22

Author(s):

Richard W. Carlson ◽

Richard C. Schaeffer ◽

Moises Carpio ◽

Max Harry Weil

Keyword(s):

Pulmonary Edema ◽

Edema Fluid

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Alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.4.1301 ◽

1999 ◽

Vol 87 (4) ◽

pp. 1301-1312 ◽

Cited By ~ 125

Author(s):

G. M. Verghese ◽

L. B. Ware ◽

B. A. Matthay ◽

M. A. Matthay

Keyword(s):

Pulmonary Edema ◽

Fluid Transport ◽

Simplified Acute Physiology Score ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Alveolar Fluid Clearance ◽

Ventricular Ejection Fraction ◽

Mechanically Ventilated ◽

Alveolar Epithelial ◽

Edema Fluid

To characterize the rate and regulation of alveolar fluid clearance in the uninjured human lung, pulmonary edema fluid and plasma were sampled within the first 4 h after tracheal intubation in 65 mechanically ventilated patients with severe hydrostatic pulmonary edema. Alveolar fluid clearance was calculated from the change in pulmonary edema fluid protein concentration over time. Overall, 75% of patients had intact alveolar fluid clearance (≥3%/h). Maximal alveolar fluid clearance (≥14%/h) was present in 38% of patients, with a mean rate of 25 ± 12%/h. Hemodynamic factors (including pulmonary arterial wedge pressure and left ventricular ejection fraction) and plasma epinephrine levels did not correlate with impaired or intact alveolar fluid clearance. Impaired alveolar fluid clearance was associated with a lower arterial pH and a higher Simplified Acute Physiology Score II. These factors may be markers of systemic hypoperfusion, which has been reported to impair alveolar fluid clearance by oxidant-mediated mechanisms. Finally, intact alveolar fluid clearance was associated with a greater improvement in oxygenation at 24 h along with a trend toward shorter duration of mechanical ventilation and an 18% lower hospital mortality. In summary, alveolar fluid clearance in humans may be rapid in the absence of alveolar epithelial injury. Catecholamine-independent factors are important in the regulation of alveolar fluid clearance in patients with severe hydrostatic pulmonary edema.

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Non-Invasive Diagnosis of the Etiology of Acute Pulmonary Edema Using the Edema Fluid-to-Plasma Protein Ratio.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a3377 ◽

2009 ◽

Author(s):

LB Ware ◽

RD Fremont ◽

JA Bastarache ◽

CS Calfee ◽

MA Matthay

Keyword(s):

Pulmonary Edema ◽

Plasma Protein ◽

Acute Pulmonary Edema ◽

Protein Ratio ◽

Non Invasive ◽

Edema Fluid

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Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00438.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. L703-L709 ◽

Cited By ~ 17

Author(s):

Angela J. Rogers ◽

Kévin Contrepois ◽

Manhong Wu ◽

Ming Zheng ◽

Gary Peltz ◽

...

Keyword(s):

Pulmonary Edema ◽

Metabolic Profiling ◽

Metabolic Profile ◽

Principal Component ◽

Distinct Group ◽

Multivariate Statistical ◽

Clinical Criteria ◽

Edema Fluid ◽

Biological Heterogeneity ◽

Physiological Heterogeneity

There is considerable biological and physiological heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a subgroup of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Nontargeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were conducted to find discriminant metabolites. Seven-hundred and sixty unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared with edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This “high metabolite” endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biological heterogeneity among ARDS patients who meet standard clinical and physiological criteria for ARDS.

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Pulmonary Edema Fluid Clearance Pathways

Physiology ◽

10.1152/physiologyonline.1995.10.3.107 ◽

1995 ◽

Vol 10 (3) ◽

pp. 107-111

Author(s):

R. E. Drake ◽

J. C. Gabel

Keyword(s):

Pulmonary Edema ◽

Lung Tissue ◽

Lymphatic Vessels ◽

Edema Fluid

Lymphatic vessels normally remove excess fluid from the lung tissue and thus prevent pulmonary edema. However, when lungs do become edematous, the edema fluid may be cleared via several pathways. Each clearance pathway has unique properties, and recent studies have helped to define those properties.

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