scholarly journals Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome

JCI Insight ◽  
2021 ◽  
Author(s):  
Alicia N. Rizzo ◽  
Sarah M. Haeger ◽  
Kaori Oshima ◽  
Yimu Yang ◽  
Alison M. Wallbank ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Alveolar Epithelial ◽  
Surfactant Dysfunction

scholarly journals Alveolar CCN1 is associated with mechanical stretch and acute respiratory distress syndrome severity

2020 ◽  
Vol 319 (5) ◽  
pp. L825-L832
Author(s):  
Eric D. Morrell ◽  
Serge Grazioli ◽  
Chi Hung ◽  
Osamu Kajikawa ◽  
Susanna Kosamo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Mechanical Stretch ◽  
Mechanically Ventilated ◽  
Alveolar Epithelial ◽  
Protein Levels

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of Ccn1 is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring 1) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), 2) Ccn1 gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and 3) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI ( n = 6) versus noninjured controls ( n = 6). Ccn1 gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS ( n = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS ( n = 45) ( P < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all P < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.

Synergistic Inhibition of β2-adrenergic Receptor–mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-β

2015 ◽  
Vol 122 (5) ◽  
pp. 1084-1092 ◽  
Author(s):  
Brant M. Wagener ◽  
Jérémie Roux ◽  
Michel Carles ◽  
Jean-Francois Pittet
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Fluid Transport ◽  
Distress Syndrome ◽  
Transforming Growth Factor ◽  
Adenosine Monophosphate ◽  
Synergistic Inhibition ◽  
Alveolar Epithelial ◽  
Tgf Β1

Abstract Background: Patients with acute respiratory distress syndrome who retain maximal alveolar fluid clearance (AFC) have better clinical outcomes. The release of endogenous catecholamines associated with shock or the administration of β2-adrenergic receptor (β2AR) agonists enhances AFC via a 3′-5′-cyclic adenosine monophosphate–dependent mechanism. The authors have previously reported that transforming growth factor-β1 (TGF-β1) and interleukin-8 (IL-8), two major mediators of alveolar inflammation associated with the early phase of acute respiratory distress syndrome, inhibit AFC upregulation by β2AR agonists via a phosphoinositol-3-kinase (PI3K)–dependent mechanism. However, whether TGF-β1 and IL-8 cause an additive or synergistic inhibition of AFC is unclear. Thus, the central hypothesis of the study was to determine whether they synergistically inhibit the β2AR-stimulated AFC by activating two different isoforms of PI3K. Methods: The effects of TGF-β1 or IL-8 on β2AR agonist–stimulated net alveolar fluid transport were studied using short-circuit current studies. Molecular pathways of inhibition were confirmed by pharmacologic inhibitors and Western blotting of p-Akt, G-protein–coupled receptor kinase 2, protein kinase C-ζ, and phospho-β2AR. Finally, our observations were confirmed by an in vivo model of AFC. Results: Combined exposure to TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 caused synergistic inhibition of β2AR agonist–stimulated vectorial Cl− across alveolar epithelial type II cells (n = 12 in each group). This effect was explained by activation of different isoforms of PI3K by TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Furthermore, the inhibitory effect of TGF-β1 on 3′-5′-cyclic adenosine monophosphate–stimulated alveolar epithelial fluid transport required the presence of IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Inhibition of cytokine-induced neutrophil chemoattractant-1 prevented TGF-β1–mediated heterologous β2AR downregulation and restored physiologic β2AR agonist–stimulated AFC in rats (n = 6 in each group). Conclusions: TGF-β1 and IL-8 have a synergistic inhibitory effect on β2AR-mediated stimulation of pulmonary edema removal by the alveolar epithelium. This result may, in part, explain why a large proportion of the patients with acute respiratory distress syndrome have impaired AFC.

scholarly journals Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergio Esquivel-Ruiz ◽  
Paloma González-Rodríguez ◽  
José A. Lorente ◽  
Francisco Pérez-Vizcaíno ◽  
Raquel Herrero ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Extracellular Vesicles ◽  
Distress Syndrome ◽  
Therapeutic Potential ◽  
Genetic Material ◽  
Capillary Barrier ◽  
Barrier Disruption ◽  
Alveolar Epithelial

Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.

scholarly journals Distinct Time Courses and Pathogenic Contributions of Alveolar Epithelial and Endothelial Injury in Acute Respiratory Distress Syndrome With COVID-19: Evidence From Circulating Biomarkers

2021 ◽  
Author(s):  
Kentaro Tojo ◽  
Natsuhiro Yamamoto ◽  
Takahiro Mihara ◽  
Miyo Abe ◽  
Takahisa Goto
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Tissue Injury ◽  
Endothelial Injury ◽  
Epithelial Injury ◽  
Alveolar Epithelial ◽  
Srage Level ◽  
Alveolar Tissue

Abstract Background: In severe cases of coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS) with alveolar tissue injury occurs. However, the time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of COVID-19 ARDS remain unclear.Methods: We evaluated the levels of a circulating alveolar epithelial injury marker (soluble receptor for advanced glycation end-products: sRAGE) and an endothelial injury marker (angiopoietin-2: ANG-2), along with an alveolar permeability indicator (surfactant protein D: SP-D) in 107 serum samples from nine patients with ARDS and eight without ARDS, all with COVID-19, admitted to Yokohama City University Hospital from January to July 2020. We compared the initial levels of these markers between ARDS and non-ARDS patients, and analysed the temporal changes of these markers in ARDS patients. Results: All the initial levels of sRAGE (median: 2680 pg/mL, IQR:1522–5076 vs. median 701 pg/mL, IQR:344–1148.0, p=0.0152), ANG-2 (median: 699 pg/mL, IQR: 410-2501 vs. median: 231 pg/mL, IQR: 64-584, p=0.0464), and SP-D (median: 17542 pg/mL, IQR: 7423-22979 vs. 1771 pg/mL, IQR: 458-204, p=0.0274) were significantly higher in the ARDS patients than in the non-ARDS patients. The peak sRAGE level in the ARDS patients was observed at the very early phase of disease progression (median: day 1, IQR: day 1–3.5). However, the peaks of ANG-2 (median: day 4, IQR: day 2.5–6) and SPD (median: day 5, IQR: day 3–7.5) were observed at a later phase. Moreover, the ANG-2 level was significantly correlated with the arterial oxygenation (p=0.030) and the SPD level (p=0.002), but the sRAGE level was not. Conclusion: Evaluation of circulating markers confirms that COVID-19 ARDS is characterised by severe alveolar tissue injury. Our data indicate that the endothelial injury, which continues for a longer period than the epithelial injury, seems to be the main contributor to alveolar barrier disruption. Targeting the endothelial injury may, thus, be a promising approach to overcome ARDS with COVID-19.

scholarly journals Distinct time courses and pathogenic contributions of alveolar epithelial and endothelial injury in acute respiratory distress syndrome with COVID-19: evidence from circulating biomarkers

2021 ◽  
Author(s):  
Kentaro Tojo ◽  
Natsuhiro Yamamoto ◽  
Takahiro Mihara ◽  
Miyo Abe ◽  
Takahisa Goto
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Tissue Injury ◽  
Endothelial Injury ◽  
Epithelial Injury ◽  
Alveolar Epithelial ◽  
Srage Level ◽  
Alveolar Tissue

AbstractBackgroundIn severe cases of coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS) with alveolar tissue injury occurs. However, the time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of COVID-19 ARDS remain unclear.MethodsWe evaluated the levels of a circulating alveolar epithelial injury marker (soluble receptor for advanced glycation end-products: sRAGE) and an endothelial injury marker (angiopoietin-2: ANG-2), along with an alveolar permeability indicator (surfactant protein D: SP-D) in 107 serum samples from nine patients with ARDS and eight without ARDS, all with COVID-19. We compared the initial levels of these markers between ARDS and non-ARDS patients, and analysed the temporal changes of these markers in ARDS patients.FindingsAll the initial levels of sRAGE, ANG-2, and SP-D were significantly higher in the ARDS patients than in the non-ARDS patients. The peak sRAGE level in the ARDS patients was observed at the very early phase of disease progression. However, the peaks of ANG-2 and SPD were observed at a later phase. Moreover, the ANG-2 level was significantly correlated with the arterial oxygenation and the SPD level, but the sRAGE level was not.InterpretationEvaluation of circulating markers confirms that COVID-19 ARDS is characterised by severe alveolar tissue injury. Our data indicate that the endothelial injury, which continues for a longer period than the epithelial injury, seems to be the main contributor to alveolar barrier disruption. Targeting the endothelial injury may, thus, be a promising approach to overcome ARDS with COVID-19.FundingNone

scholarly journals Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome

2009 ◽  
Vol 297 (6) ◽  
pp. L1035-L1041 ◽  
Author(s):  
Julie A. Bastarache ◽  
Richard D. Fremont ◽  
Jonathan A. Kropski ◽  
Frederick R. Bossert ◽  
Lorraine B. Ware
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Pulmonary Edema ◽  
Distress Syndrome ◽  
Alveolar Epithelium ◽  
Procoagulant Activity ◽  
Alveolar Epithelial ◽  
Potential Source ◽  
Air Space

Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. In the vascular space, TF-bearing microparticles (MPs) are central to clot formation and propagation. We hypothesized that TF-bearing MPs in the lungs of patients with ARDS contribute to the procoagulant phenotype in the air space during acute injury and that the alveolar epithelium is one potential source of TF MPs. We studied pulmonary edema fluid collected from patients with ARDS compared with a control group of patients with hydrostatic pulmonary edema. Patients with ARDS have higher concentrations of MPs in the lung compared with patients with hydrostatic edema (25.5 IQR 21.3–46.9 vs. 7.8 IQR 2.3–27.5 μmol/l, P = 0.009 by Mann-Whitney U-test). These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.

Pathophysiology of acute respiratory distress syndrome

2016 ◽  
Author(s):  
Lorraine B. Ware
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Pulmonary Oedema ◽  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Cigarette Smoke Exposure ◽  
Alveolar Epithelial ◽  
Severe Traumatic Injury

The acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by the acute onset of non-cardiogenic pulmonary oedema due to increased lung endothelial and alveolar epithelial permeability. Common predisposing clinical conditions include sepsis, pneumonia, severe traumatic injury, and aspiration of gastric contents. Environmental factors, such as alcohol abuse and cigarette smoke exposure may increase the risk of developing ARDS in those at risk. Pathologically, ARDS is characterized by diffuse alveolar damage with neutrophilic alveolitis, haemorrhage, hyaline membrane formation, and pulmonary oedema. A variety of cellular and molecular mechanisms contribute to the pathophysiology of ARDS, including exuberant inflammation, neutrophil recruitment and activation, oxidant injury, endothelial activation and injury, lung epithelial injury and/or necrosis, and activation of coagulation in the airspace. Mechanical ventilation can exacerbate lung inflammation and injury, particularly if delivered with high tidal volumes and/or pressures. Resolution of ARDS is complex and requires coordinated activation of multiple resolution pathways that include alveolar epithelial repair, clearance of pulmonary oedema through active ion transport, apoptosis, and clearance of intra-alveolar neutrophils, resolution of inflammation and fibrinolysis of fibrin-rich hyaline membranes. In some patients, activation of profibrotic pathways leads to significant lung fibrosis with resultant prolonged respiratory failure and failure of resolution.

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