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.

High Expression of CXCL10/CXCR3 in Ventilator-Induced Lung Injury Caused by High Mechanical Power

Background. The energy delivered by a ventilator to the respiratory system in one minute is defined as mechanical power (MP). However, the effect of ventilator-induced lung injury (VILI) in patients suffering from acute respiratory distress syndrome (ARDS) is still unknown. Our previous studies revealed that CXCL10 may be a potential biomarker of lung injury in ARDS. Therefore, the aim of this study was to compare the lung injury of rats and patients under different MP conditions to explore the involvement of CXCL10 and its receptor CXCR3 in VILI. Methods. Patients were divided into the high mechanical power group (HMPp group) and low mechanical power group (LMPp group), while rats were assigned to the high mechanical power group (HMPr group), medium mechanical power group (MMPr group), and low mechanical power group (LMPr group). CXCL10 and CXCR3 plasma content in ARDS patients and rats under ventilation at different MP was measured, as well as their protein and mRNA expression in rat lungs. Results. CXCL10 and CXCR3 content in the plasma of ARDS patients in the HMPp was significantly higher than that in the LMPp. The increase of MP during mechanical ventilation in the rats gradually increased lung damage, and CXCL10 and CXCR3 levels in rat plasma gradually increased with the increase of MP. CXCL10 and CXCR3 protein and mRNA expression in the HMPr group and MMPr group was significantly higher than that in the LMPr group ( P < 0.05 ). More mast cells were present in the trachea, bronchus, blood vessels, and lymphatic system in the rat lungs of the HMPr group, and the number of mast cells in the HMPr group ( 13.32 ± 3.27 ) was significantly higher than that in the LMPr group ( 3.25 ± 0.29 ) ( P < 0.05 ). Conclusion. The higher the MP, the more severe the lung injury, and the higher the CXCL10/CXCR3 expression. Therefore, CXCL10/CXCR3 might participate in VILI by mediating mast cell chemotaxis.

Neutrophil-Derived IL-17 Promotes Ventilator-Induced Lung Injury via p38 MAPK/MCP-1 Pathway Activation

Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation and can severely affect health. VILI appears to involve excessive inflammatory responses, but its pathogenesis has not yet been clarified. Since interleukin-17 (IL-17) plays a critical role in the immune system and the development of infectious and inflammatory diseases, we investigated here whether it plays a role in VILI. In a mouse model of VILI, mechanical ventilation with high tidal volume promoted the accumulation of lung neutrophils, leading to increased IL-17 levels in the lung, which in turn upregulated macrophage chemoattractant protein-1 via p38 mitogen-activated protein kinase. Depletion of neutrophils decreases the production IL-17 in mice and inhibition of IL-17 significantly reduced HTV-induced lung injury and inflammatory response. These results were confirmed in vitro using RAW264.7 macrophage cultures. Our results suggest that IL-17 plays a pro-inflammatory role in VILI and could serve as a new target for its treatment.

New Frontiers in Functional and Molecular Imaging of the Acutely Injured Lung: Pathophysiological Insights and Research Applications

This review focuses on the advances in the understanding of the pathophysiology of ventilator-induced and acute lung injury that have been afforded by technological development of imaging methods over the last decades. Examples of such advances include the establishment of regional lung mechanical strain as a determinant of ventilator-induced lung injury, the relationship between alveolar recruitment and overdistension, the regional vs. diffuse nature of pulmonary involvement in acute respiratory distress syndrome (ARDS), the identification of the physiological determinants of the response to recruitment interventions, and the pathophysiological significance of metabolic alterations in the acutely injured lung. Taken together, these advances portray multimodality imaging as the next frontier to both advance knowledge of the pathophysiology of these conditions and to tailor treatment to the individual patient’s condition.

Extra Corporeal Membrane Oxygenation in the Treatment of Human Immunodeficiency Virus-Related P. jirovecii Pneumonia

Despite the undeniable complexity one may encounter while managing critically ill patients with human immunodeficiency virus infection (HIV), intensive care unit-related mortality has declined in recent years, not only because of more efficacious antiretroviral therapy (ART) but also due to the advances in critical support. However, the use of extracorporeal membrane oxygenation (ECMO) in these patients remains controversial. We report four cases of HIV-infected patients with Pneumocystis jirovecii pneumonia (PJP) and acute respiratory distress syndrome (ARDS) treated with ECMO support and discuss its indications and possible role in the prevention of barotrauma and ventilator- induced lung injury (VILI). The eventually favorable clinical course of the patients that we present suggests that although immune status is an important aspect in the decision to initiate ECMO support, this technology can provide real benefit in some patients with severe HIV-related refractory ARDS.