CRISPLD2 (LGL1) inhibits proinflammatory mediators in human fetal, adult, and COPD lung fibroblasts and epithelial cells

• Published in: Physiological reports 2016-09, Vol.4 (17), p.e12942-n/a
• Main Authors: Zhang, Hui, Kho, Alvin T., Wu, Qing, Halayko, Andrew J., Limbert Rempel, Karen, Chase, Robert P., Sweezey, Neil B., Weiss, Scott T., Kaplan, Feige
• Format: Article
• Language: English
• Subjects: Adult; Aged; Ageing and Degeneration; Animals; Apoptosis; Asthma; Bronchopulmonary dysplasia (BPD); Bronchopulmonary Dysplasia - embryology; Bronchopulmonary Dysplasia - metabolism; Bronchopulmonary Dysplasia - pathology; Cell adhesion & migration; Cell Adhesion Molecules - deficiency; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell division; Cell migration; Cell Proliferation - physiology; Cells, Cultured; Cellular Physiology; Chemokines; Children; Chronic obstructive pulmonary disease; Cloning; CRISPLD2 (LGL1); Dysplasia; Elastin; Embryos; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - physiology; Extracellular matrix; Fetuses; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Fibroblasts - pathology; Genes; Glucocorticoids; HEK293 Cells; human fetal/adult lung fibroblast; Humans; Hypotheses; Immunology; Inflammation; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interleukin-6 - metabolism; Investigations; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lung - cytology; Lung - embryology; Lung - metabolism; Lung - pathology; Lung diseases; Male; Maternal, Fetal and Neonatal Physiology; mesenchymal–epithelial interaction; Mesenchyme; Mice; Middle Aged; Monocyte chemoattractant protein 1; Morbidity; Neonates; Newborn babies; Obstructive lung disease; Original Research; Pathogenesis; Physiology; Premature birth; pro/antiinflammation; Proteins; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Respiratory Conditions Disorder and Diseases; Respiratory diseases; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Signal Transduction; siRNA
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.12942

Chronic lung disease of prematurity/bronchopulmonary dysplasia (BPD) is the leading cause of perinatal morbidity in developed countries. Inflammation is a prominent finding. Currently available interventions have associated toxicities and limited efficacy. While BPD often resolves in childhood, survivors of preterm birth are at risk for acquired respiratory disease in early life and are more likely to develop chronic obstructive pulmonary disease (COPD) in adulthood. We previously cloned Crispld2 (Lgl1), a glucocorticoid‐regulated mesenchymal secretory protein that modulates lung branching and alveogenesis through mesenchymal–epithelial interactions. Absence of Crispld2 is embryonic lethal. Heterozygous Crispld2+/− mice display features of BPD, including distal airspace enlargement, disruption of elastin, and neonatal lung inflammation. CRISPLD2 also plays a role in human fetal lung fibroblast cell expansion, migration, and mesenchymal–epithelial signaling. This study assessed the effects of endogenous and exogenous CRISPLD2 on expression of proinflammatory mediators in human fetal and adult (normal and COPD) lung fibroblasts and epithelial cells. CRISPLD2 expression was upregulated in a lipopolysaccharide (LPS)‐induced human fetal lung fibroblast line (MRC5). LPS‐induced upregulation of the proinflammatory cytokines IL‐8 and CCL2 was exacerbated in MRC5‐CRISPLD2knockdown cells. siRNA suppression of endogenous CRISPLD2 in adult lung fibroblasts (HLFs) led to augmented expression of IL‐8, IL‐6, CCL2. LPS‐stimulated expression of proinflammatory mediators by human lung epithelial HAEo‐ cells was attenuated by purified secretory CRISPLD2. RNA sequencing results from HLF‐CRISPLD2knockdown suggest roles for CRISPLD2 in extracellular matrix and in inflammation. Our data suggest that suppression of CRISPLD2 increases the risk of lung inflammation in early life and adulthood. This study assessed the effects of CRISPLD2 on expression of proinflammatory mediators in human fetal and adult (normal and chronic obstructive pulmonary disease) lung fibroblast and epithelial cells. Our data show that suppression of CRISPLD2 increases the risk of lung inflammation in both early life and in adulthood. Lipopolysaccharide‐stimulated expression of proinflammatory mediators by human lung epithelial cells was attenuated by purified secretory CRISPLD2. Given the paucity of available and effective prevention and treatment for the profound burden of neonatal lung injury, investigati