Bentley, I. D. | Search bioRxiv

bioRxiv2026

Annexin A2 Regulates Surfactant Dysfunction During Injurious Ventilation.

The Acute Respiratory Distress Syndrome (ARDS) is a life-threatening cause of respiratory failure, and patients who develop ARDS frequently require mechanical ventilation, which puts them at risk of developing ventilator induced lung injury (VILI). Both VILI and ARDS can induce pulmonary surfactant dysfunction, but the mechanisms are not known. Here we report a novel role for a phospholipid binding protein, Annexin A2 (AnxA2), in the regulation of surfactant composition and function following injurious ventilation. Wild type and AnxA2-/-mice were subjected to injurious ventilation and we found that AnxA2-/- mice developed stiffer lungs following VILI that was not due to differences in barrier permeability or inflammation. Furthermore, we found that pulmonary surfactant from AnxA2-/- mice had reduced surface tension lowering properties and that this was due to a reduction in 1-palmitoyl-2-oleoylphosphatidylglycerol, or POPG. Quantitative analysis of surface tension-surface area hysteresis loops obtained from surfactant isolated from AnxA2-/- mice showed a defect in phase transitions during compression. In summary, Annexin A2 regulates surfactant function during injurious ventilation and may serve as a novel therapeutic target to prevent surfactant dysfunction in patients with ARDS who require mechanical ventilation.

molecular biology↗

bioRxiv2024

scRNA-seq identifies unique macrophage population in murine model of ozone induced asthma exacerbation

Ozone (O3) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms by which this occurs are unknown. Previously, we developed a murine model of dust mite, ragweed, and aspergillus (DRA)-induced allergic lung inflammation followed by O3 exposure for mechanistic investigation. The present study used single cell RNA-sequencing for unbiased profiling of immune cells within the lungs of mice exposed to DRA, O3, or DRA+O3, to identify the components of the immune cell niche that contribute to AHR. Alveolar macrophages (AMs) had the greatest number of differentially expressed genes following DRA+O3, most of which were unique to the 2-hit exposure. Following DRA+O3, AMs activated transcriptional pathways related to cholesterol biosynthesis, degradation of the extracellular matrix, endosomal TLR processing, and various cytokine signals. We also identified AM and monocyte subset populations that were unique to the DRA+O3 group. These unique AMs activated gene pathways related to inflammation, sphingolipid metabolism, and bronchial constriction. The unique monocyte population had a gene signature that suggested phospholipase activation and increased degradation of the extracellular matrix. Flow cytometry analysis of BAL immune cells showed recruited monocyte-derived AMs after DRA and DRA+O3, but not after O3 exposure alone. O3 alone increased BAL neutrophils but this response was attenuated in DRA+O3 mice. DRA-induced changes in the airspace immune cell profile were reflected in elevated BAL cytokine/chemokine levels following DRA+O3 compared to O3 alone. The present work highlights the role of monocytes and AMs in the response to O3 and suggests that the presence of distinct subpopulations following allergic inflammation may contribute to O3-induced AHR.

pharmacology and toxicology↗