Disruption of the surfactant protein A receptor isoform SP-R210L in alveolar macrophages alters airway, vascular, and immune homeostasis in the lung

Abstract

Surfactant protein A modulates alveolar macrophage activation and pathogen clearance through the receptor SP-R210, which consists of a homeostatic SP-R210L and an inflammatory SP-R210S isoform in alveolar macrophages (AMs). Both isoforms are encoded from alternatively spliced mRNAs of the Myo18α/MYO18Aα gene in mice and humans. The objective of this study is to elucidate the functions of SP-R210 isoforms in AM function in vivo. We hypothesized that disruption of SP-R210L in AMs would alter the local microenvironment. To address this hypothesis in vivo, we generated conditional transgenic mice by targeting exon 1 encoding the unique amino-terminal KE/PDZ domain of SP-R210L. This strategy enabled selective deletion of SP-R210L in AMs via ITGAXCre-mediated inversion recombination. The impact of AM selective deletion of SP-R210L was studied by histological, biochemical, flow cytometric, and respiratory mechanics measurements in young and aged mice. Airway hyperresponsiveness was measured during exposure to escalating doses of methacholine. These studies show that conditional disruption of SP-R210L results in pulmonary disease consisting of hemosiderin deposition in AMs, decline in long-term maintenance of AMs and lung immune cells, obstructive-restrictive pulmonary mechanics, increased airway hyper-responsiveness, alteration in small solute permeability, arterial smooth muscle hyperplasia and inflammation. Our findings support the novel idea that SP-R210L modulates paracrine functions of AMs in maintenance of alveolar- and airway-capillary homeostasis in the lung. SP-R210L dysfunction may increase the risk for development of pulmonary hypertension. Department of Pediatrics, Penn State College of Medicine, The Children's Miracle Network, NIH HL128746 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.