ABSTRACT
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 acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes 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 - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits ß-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize ß-catenin signaling, thereby limiting progenitor function. Constitutive activation of ß-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.
Subject(s)
Hypercapnia , Wnt Signaling Pathway , Mice , beta Catenin/metabolism , Cell Proliferation , COVID-19/complications , Hypercapnia/metabolismSubject(s)
COVID-19 , Electrocardiography/methods , Respiratory Insufficiency , Thrombophilia , Adult , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Clinical Deterioration , Computed Tomography Angiography/methods , Fatal Outcome , Female , Heart Arrest/etiology , Heart Arrest/therapy , Humans , Patient Care Management/methods , Pulmonary Embolism/diagnosis , Pulmonary Embolism/etiology , Respiration, Artificial/methods , Respiratory Insufficiency/blood , Respiratory Insufficiency/etiology , Respiratory Insufficiency/physiopathology , Respiratory Insufficiency/therapy , SARS-CoV-2/isolation & purification , Thrombophilia/blood , Thrombophilia/etiology , Thrombophilia/physiopathology , Thrombophilia/therapy , Ventricular Dysfunction/diagnosis , Ventricular Dysfunction/etiologyABSTRACT
Several cases have recently been reported concerning the development of a syndrome of acute lung injury associated with the use of electronic cigarettes, leading to respiratory failure and several deaths. We present a case of a young veteran who presented with e-cigarette vaping associated lung injury (EVALI) to a primary care clinic and who required subsequent inpatient admission and home oxygen therapy after discharge. The patient afterwards improved after a three-month course of steroids and cessation of THC-containing electronic cigarettes, consistent with previously reported cases. Furthermore, evidence on bronchoscopy and biopsy demonstrated intracellular lipid droplets in the patient's macrophages. This outpatient case of EVALI prompts primary care providers to raise suspicion of this condition, and enquire about the use of e-cigarettes, particularly THC-containing vaping products. Furthermore, in the setting of the COVID-19 pandemic, similar clinical and radiographic presentations between COVID-19 and EVALI can be seen.