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

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.

Superimposed High Frequency Jet Ventilation Minimises Diaphragm, Bronchus, and Mediastinum Motion during One-Lung Flooding

Background: One-Lung Flooding (OLF) represents an ideal acoustic pathway for focused ultrasound ablation of lung tumours. Despite stabilization of the adjacent hemidiaphragm by OLF, standard Pressure-Controlled Ventilation (PCV) of the contralateral lung causes an unacceptable movement of the flooded lung. We examined whether Superimposed High Frequency Jet Ventilation (SHFJV) reduces lung motion compared to PCV during OLF. Methods: The study included 15 pigs: 10 underwent OLF; 5 controls underwent two-lung ventilation without OLF. Using ultrasound, diaphragm displacement on the flooded lung side was measured during PCV and SHFJV in the left lateral (LLP), Supine (SP), and Right Lateral Positions (RLP). Bronchus and mediastinum displacements were measured in the right lateral position. Results: Diaphragm displacement on the flooded lung side was significantly reduced during SHFJV, compared with PCV, in all animal positions (LLP: 7mm [4.75-8.0] vs. 17mm [14.75-19.0], P=0.0039; SP: 4mm [3.75-4.25] vs. 17mm [16.0–18.5], P=0.0039; RLP: 8mm [5.75-9.0] vs. 20mm [14.0-23.25], P=0.0078). Displacement of both the bronchus and mediastinum were significantly reduced during SHFJV, compared with PCV, in RLP (bronchus: 2.0mm [1.75-2.25] vs. 3.0mm [2.75-3.0], P=0.027; mediastinum: 4.5mm [4.0-5.0] vs. 10mm [7.0-10.0], P=0.0078. Conclusion: Thus, SHFJV minimises diaphragm, bronchus, and mediastinum motion during OLF, which is a prerequisite for effective lung tumour ablation.

Superimposed high-frequency jet ventilation minimises diaphragm, bronchus, and mediastinum motion during one-lung flooding

Background: One-lung flooding (OLF) represents an ideal acoustic pathway for focused ultrasound ablation of lung tumours. Despite stabilization of the adjacent hemidiaphragm by OLF, standard pressure-controlled ventilation (PCV) of the contralateral lung causes an unacceptable movement of the flooded lung. We examined whether superimposed high-frequency jet ventilation (SHFJV) reduces lung motion compared to PCV during OLF.Methods: The study included 15 pigs: 10 underwent OLF; 5 controls underwent two-lung ventilation without OLF. Using ultrasound, diaphragm displacement on the flooded lung side was measured during PCV and SHFJV in the left lateral (LLP), supine (SP), and right lateral positions (RLP). Bronchus and mediastinum displacements were measured in the right lateral position. Results: Diaphragm displacement on the flooded lung side was significantly reduced during SHFJV, compared with PCV, in all animal positions (LLP: 7 mm [4.75–8.0] vs. 17 mm [14.75–19.0], P = 0.0039; SP: 4 mm [3.75–4.25] vs. 17 mm [16.0–18.5], P = 0.0039; RLP: 8 mm [5.75–9.0] vs. 20 mm [14.0–23.25], P = 0.0078). Displacement of both the bronchus and mediastinum were significantly reduced during SHFJV, compared with PCV, in RLP (bronchus: 2.0 mm [1.75–2.25] vs. 3.0 mm [2.75–3.0], P = 0.027; mediastinum: 4.5 mm [4.0–5.0] vs. 10 mm [7.0–10.0], P = 0.0078; Figs. 5, 6). Conclusion: Thus, SHFJV minimises diaphragm, bronchus, and mediastinum motion during OLF, which is a prerequisite for effective lung tumour ablation.

Feasibility of MR guided Lung Cancer ablation using saline flooded lung

Lung cancer is the most mortal tumor entity, which is preferably treated by surgical resection. Alternative ablation methods (rf, litt) haven't been clinically established by their invasivity. HIFU is not considered as an treatment option in lung due to the air content. Lung flooding generates gas free saline parenchyma compound without damaging the lung. Recently our work showed the usability of ultrasound guided lung cancer hifu ablation. In contrast to ultrasound, MRg-FUS would improve the radically of treatment. Toward the first human pilot, the lung flooding process needs to be optimized for operating in MR environment. Further the usability of MR imaging and thermometry in flooded lung haven't been investigated so far. This research project is aimed to provide fundamental information describing the usability and limitations of MRg-FUS treatment of lung cancer using lung flooding.