scholarly journals Hypercapnia limits β-catenin mediated alveolar type 2 cell progenitor function by altering Wnt production from adjacent fibroblasts

2022 ◽  
Author(s):  
Laura A Dada ◽  
Lynn C Welch ◽  
Natalia D Magnani ◽  
Ziyou Ren ◽  
Patricia L Brazee ◽  
...  
Keyword(s):  
Alveolar Type ◽  
Mechanically Ventilated ◽  
Persistent Symptoms ◽  
Low Tidal Volume ◽  
Lung Repair ◽  
Ventilator Induced Lung Injury ◽  
Lung Flooding ◽  
Volume Ventilation

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with ARDS secondary to SARS-CoV-2 pneumonia, low tidal volume ventilation to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here, we show that hypercapnia limits β-catenin signaling in alveolar type 2 (AT2) cells, leading to reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα-fibroblasts from those maintaining AT2 progenitor activity and towards those that antagonize β-catenin signaling and limit progenitor function. Activation of β-catenin signaling in AT2 cells, rescues the effects of hypercapnia on proliferation. Inhibition of AT2 proliferation in hypercapnic patients may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier, increasing lung flooding, ventilator dependency and mortality.

scholarly journals Management of hypercapnia in critically ill mechanically ventilated patients—A narrative review of literature

2020 ◽  
Vol 21 (4) ◽  
pp. 327-333
Author(s):  
Ravindranath Tiruvoipati ◽  
Sachin Gupta ◽  
David Pilcher ◽  
Michael Bailey
Keyword(s):  
Mechanical Ventilation ◽  
Tidal Volume ◽  
Dead Space ◽  
Hypercapnic Acidosis ◽  
Mechanically Ventilated ◽  
Mechanically Ventilated Patients ◽  
Low Tidal Volume ◽  
Volume Ventilation ◽  
Low Volume ◽  
Ventilated Patients

The use of lower tidal volume ventilation was shown to improve survival in mechanically ventilated patients with acute lung injury. In some patients this strategy may cause hypercapnic acidosis. A significant body of recent clinical data suggest that hypercapnic acidosis is associated with adverse clinical outcomes including increased hospital mortality. We aimed to review the available treatment options that may be used to manage acute hypercapnic acidosis that may be seen with low tidal volume ventilation. The databases of MEDLINE and EMBASE were searched. Studies including animals or tissues were excluded. We also searched bibliographic references of relevant studies, irrespective of study design with the intention of finding relevant studies to be included in this review. The possible options to treat hypercapnia included optimising the use of low tidal volume mechanical ventilation to enhance carbon dioxide elimination. These include techniques to reduce dead space ventilation, and physiological dead space, use of buffers, airway pressure release ventilation and prone positon ventilation. In patients where hypercapnic acidosis could not be managed with lung protective mechanical ventilation, extracorporeal techniques may be used. Newer, minimally invasive low volume venovenous extracorporeal devices are currently being investigated for managing hypercapnia associated with low and ultra-low volume mechanical ventilation.

scholarly journals Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repair

2020 ◽  
Author(s):  
Ali Gibran ◽  
Runzhen Zhao ◽  
Mo Zhang ◽  
Krishan G. Jain ◽  
Jianjun Chang ◽  
...  
Keyword(s):  
Alveolar Epithelium ◽  
Influenza Viruses ◽  
Alveolar Type ◽  
Differential Rate ◽  
Alveolar Epithelial ◽  
Proliferation And Differentiation ◽  
Marked Suppression

ABSTRACTCOVID-19, SARS, and MERS are featured by fibrinolytic dysfunction. To test the role of the fibrinolytic niche in the regeneration of alveolar epithelium, we compared the self-renewing capacity of alveolar epithelial type 2 (AT2) cells and its differentiation to AT1 cells between wild type (wt) and fibrinolytic niche deficient mice (Plau−/− and Serpine1Tg). A significant reduction in both proliferation and differentiation of deficient AT2 cells was observed in vivo and in 3D organoid cultures. This decrease was mainly restored by uPA derived A6 peptide, a binding fragment to CD44 receptors. The proliferative and differential rate of CD44+ AT2 cells was greater than that of CD44− controls. There was a reduction in transepithelial ion transport in deficient monolayers compared to wt cells. Moreover, we found a marked suppression in total AT2 cells and CD44+ subpopulation in lungs from brain dead patients with acute respiratory distress syndrome (ARDS) and a mouse model infected by influenza viruses. Thus, we demonstrate that the fibrinolytic niche can regulate AT2-mediated homeostasis and regeneration via a novel uPA-A6-CD44+-ENaC cascade.

scholarly journals Pneumomediastinum secondary to invasive and non-invasive mechanical ventilation

2019 ◽  
Vol 7 (27) ◽  
pp. 36-42 ◽  
Author(s):  
Sara Mousa ◽  
Hawa Edriss
Keyword(s):  
Mechanical Ventilation ◽  
Tidal Volume ◽  
Distress Syndrome ◽  
Invasive Mechanical Ventilation ◽  
X Rays ◽  
Mechanically Ventilated ◽  
Non Invasive ◽  
Low Tidal Volume ◽  
Volume Ventilation ◽  
High Frequency Oscillatory

Pneumomediastinum (PM) is defined as the presence of abnormal gas in the mediastinum.It is a known complication of invasive mechanical ventilation and has been reported withnon-invasive ventilation. Recent studies have reported that the incidence of barotrauma islowest in post-operative patients and is highest in mechanically ventilated patients with acuterespiratory distress syndrome. The incidence has dropped with the low tidal volume ventilationtechnique. Chest x-rays can miss up to 25% of small PMs detected by computed tomographyscans of the chest. Pneumomediastinum is managed with low tidal volume ventilation withplateau pressures <30 cm H2O and treatment of the underlying lung disease. Novel ways ofventilation, such as high frequency oscillatory ventilation and asynchronous independent lungventilation, may improve ventilation in some patients.

Regulation of rat alveolar type 2 cell proliferation in vitro involves type II cAMP-dependent protein kinase

2007 ◽  
Vol 292 (1) ◽  
pp. L232-L239 ◽  
Author(s):  
Jan T. Samuelsen ◽  
Per E. Schwarze ◽  
Henrik S. Huitfeldt ◽  
E. Vibeke Thrane ◽  
Marit Låg ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Alveolar Type ◽  
Regulatory Subunits ◽  
Anchoring Protein ◽  
Dependent Protein ◽  
Cycle Dependent ◽  
Proliferation In Vitro

To elucidate the role of cAMP and different cAMP-dependent protein kinases (PKA; A-kinase) in lung cell proliferation, we investigated rat alveolar type 2 cell proliferation in relation to activation or inhibition of PKA and PKA regulatory subunits (RIIα and RIα). Both the number of proliferating type 2 cells and the level of different regulatory subunits varied during 7 days of culture. The cells exhibited a distinct peak of proliferation after 5 days of culture. This proliferation peak was preceded by a rise in RIIα protein level. In contrast, an inverse relationship between RIα and type 2 cell proliferation was noted. Activation of PKA increased type 2 cell proliferation if given at peak RIIα expression. Furthermore, PKA inhibitors lowered the rate of proliferation only when a high RII level was observed. An antibody against the anchoring region of RIIα showed cell cycle-dependent binding in contrast to antibodies against other regions, possibly related to altered binding to A-kinase anchoring protein. Following activation of PKA, relocalization of RIIα was confirmed by immunocytochemistry. In conclusion, it appears that activation of PKA II is important in regulation of alveolar type 2 cell proliferation.

scholarly journals Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT-mediated NAD metabolism

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaofan Lai ◽  
Shaojie Huang ◽  
Sijia Lin ◽  
Lvya Pu ◽  
Yaqing Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Potential ◽  
Alveolar Type ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Nad Metabolism

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive deadly fibrotic lung disease with high prevalence and mortality worldwide. The therapeutic potential of mesenchymal stem cells (MSCs) in pulmonary fibrosis may be attributed to the strong paracrine, anti-inflammatory, anti-apoptosis and immunoregulatory effects. However, the mechanisms underlying the therapeutic effects of MSCs in IPF, especially in terms of alveolar type 2 (AT2) cells senescence, are not well understood. The purpose of this study was to evaluate the role of MSCs in NAD metabolism and senescence of AT2 cells in vitro and in vivo. Methods MSCs were isolated from human bone marrow. The protective effects of MSCs injection in pulmonary fibrosis were assessed via bleomycin mouse models. The senescence of AT2 cells co-cultured with MSCs was evaluated by SA-β-galactosidase assay, immunofluorescence staining and Western blotting. NAD+ level and NAMPT expression in AT2 cells affected by MSCs were determined in vitro and in vivo. FK866 and NAMPT shRNA vectors were used to determine the role of NAMPT in MSCs inhibiting AT2 cells senescence. Results We proved that MSCs attenuate bleomycin-induced pulmonary fibrosis in mice. Senescence of AT2 cells was alleviated in MSCs-treated pulmonary fibrosis mice and when co-cultured with MSCs in vitro. Mechanistic studies showed that NAD+ and NAMPT levels were rescued in AT2 cells co-cultured with MSCs and MSCs could suppress AT2 cells senescence mainly via suppressing lysosome-mediated NAMPT degradation. Conclusions MSCs attenuate AT2 cells senescence by upregulating NAMPT expression and NAD+ levels, thus exerting protective effects in pulmonary fibrosis.

scholarly journals Prevalence and Outcomes of Acute Hypoxaemic Respiratory Failure in Wales: The PANDORA-WALES Study

2020 ◽  
Vol 9 (11) ◽  
pp. 3521
Author(s):  
Maja Kopczynska ◽  
Ben Sharif ◽  
Richard Pugh ◽  
Igor Otahal ◽  
Peter Havalda ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Distress Syndrome ◽  
Inclusion Criteria ◽  
Mechanically Ventilated ◽  
Patient Demographics ◽  
Low Tidal Volume ◽  
Icu Stay ◽  
Volume Ventilation ◽  
Ventilatory Management ◽  
Definition Of

Background: We aimed to identify the prevalence of acute hypoxaemic respiratory failure (AHRF) in the intensive care unit (ICU) and its associated mortality. The secondary aim was to describe ventilatory management as well as the use of rescue therapies. Methods: Multi-centre prospective study in nine hospitals in Wales, UK, over 2-month periods. All patients admitted to an ICU were screened for AHRF and followed-up until discharge from the ICU. Data were collected from patient charts on patient demographics, clinical characteristics, management and outcomes. Results: Out of 2215 critical care admissions, 886 patients received mechanical ventilation. A total of 197 patients met inclusion criteria and were recruited. Seventy (35.5%) were non-survivors. Non-survivors were significantly older, had higher SOFA scores and received more vasopressor support than survivors. Twenty-five (12.7%) patients who fulfilled the Berlin definition of acute respiratory distress syndrome (ARDS) during the ICU stay without impact on overall survival. Rescue therapies were rarely used. Analysis of ventilation showed that median Vt was 7.1 mL/kg PBW (IQR 5.9–9.1) and 21.3% of patients had optimal ventilation during their ICU stay. Conclusions: One in four mechanically ventilated patients have AHRF. Despite advances of care and better, but not optimal, utilisation of low tidal volume ventilation, mortality remains high.

scholarly journals Neutrophil Extracellular Traps Are Pathogenic in Ventilator-Induced Lung Injury and Partially Dependent on TLR4

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Haosi Li ◽  
Pinhua Pan ◽  
Xiaoli Su ◽  
Shuai Liu ◽  
Lemeng Zhang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Neutrophil Extracellular Traps ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Mechanically Ventilated ◽  
Extracellular Traps ◽  
Ventilator Induced Lung Injury ◽  
Dnase Treatment

The pathogenesis of ventilator-induced lung injury (VILI) is associated with neutrophils. Neutrophils release neutrophil extracellular traps (NETs), which are composed of DNA and granular proteins. However, the role of NETs in VILI remains incompletely understood. Normal saline and deoxyribonuclease (DNase) were used to study the role of NETs in VILI. To further determine the role of Toll-like receptor 4 (TLR4) in NETosis, we evaluated the lung injury and NET formation in TLR4 knockout mice and wild-type mice that were mechanically ventilated. Some measures of lung injury and the NETs markers were significantly increased in the VILI group. DNase treatment markedly reduced NETs markers and lung injury. After high-tidal mechanical ventilation, the NETs markers in the TLR4 KO mice were significantly lower than in the WT mice. These data suggest that NETs are generated in VILI and pathogenic in a mouse model of VILI, and their formation is partially dependent on TLR4.

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