Early-life bacterial exposure affects lung surfactant gene-expression, surfactant function and respiratory rate compared to germ-free mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201075 | GEO | 2023/01/01
REPOSITORIES: GEO
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Project description:Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in ARDS patients. Using mass spectrometry of airspace fluid noninvasively collected from mechanically-ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.
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Project description:Respiratory viral infections in early life are associated with the development of lung diseases that can persist into adulthood, but the underlying mechanisms are not well understood.We aimed to characterise virus-induced changes to pulmonary gene networks that are linked to impairement of lung development and function. Male and female BALB/c mice were inoculated at seven days of life with either Influenza A/Puerto Rico/8/34 (H1N1), Influenza A/Memphis/1/71 (H3N2) or phosphate buffered saline (PBS), and randomly sacrificed seven, fourteen and twenty-eight days post inoculation. Bulk RNAseq was performed on whole lung tissue for each sex, experimental group and timepoint.
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Project description:Aim: To establish the impact of oxygen requirement before surfactant (SF) and time from birth to SF administration on treatment outcomes in neonatal respiratory distress syndrome (RDS). Methods: We conducted a post-hoc analysis of data from a prospective cohort study of 500 premature infants treated with less invasive surfactant administration (LISA). LISA failure was defined as the need for early (<72 h of life) mechanical ventilation (MV). Baseline clinical characteristic parameters, time to SF, and fraction of inspired oxygen (FiO2) prior to SF were all included in the multifactorial logistic regression model that explained LISA failure. Results: LISA failed in 114 of 500 infants (22.8%). The median time to SF was 2.1 h (IQR: 0.8-6.7), and the median FiO2 prior to SF was 0.40 (IQR: 0.35-0.50). Factors significantly associated with LISA failure were FiO2 prior to SF (OR 1.03, 95% CI 1.01-1.04) and gestational age (OR 0.82, 95 CI 0.75-0.89); both p <0.001. Time to SF was not an independent risk factor for therapy failure (p = 0.528) or the need for MV at any time during hospitalization (p = 0.933). Conclusions: The FiO2 before SF, but not time to SF, influences the need for MV in infants with RDS. While our findings support the relevance of FiO2 in SF prescription, better adherence to the recommended FiO2 threshold for SF (0.30) is required in daily practice.
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Project description:Study the Role of Surfactant Protein C in Innate Lung Defense.
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Project description:Lysosome-associated membrane glycoprotein 3 (LAMP3) is a type I transmembrane protein of the LAMP protein family with a cell-type-specific expression in alveolar type II cells in mice and hitherto unknown function. In type II pneumocytes, LAMP3 is localized in lamellar bodies, secretory organelles releasing pulmonary surfactant into the extracellular space to lower surface tension at the air/liquid interface. The physiological function of LAMP3, however, remains enigmatic. We generated Lamp3 knockout mice by CRISPR/Cas9. LAMP3 deficient mice are viable with an average life span and display regular lung function under basal conditions. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. In ovalbumin-induced experimental allergic asthma, the changes in lipid composition are aggravated, and LAMP3-deficient mice exert an increased airway resistance. Our data suggest a critical role of LAMP3 in the regulation of pulmonary surfactant homeostasis and normal lung function.
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Project description:Surfactant protein D (SP-D) is a multimeric collectin that is involved in innate immune defense and expressed in pulmonary, as well as non-pulmonary, epithelia. SP-D exerts antimicrobial effects and dampens inflammation through direct microbial interactions and modulation of host cell responses via a series of cellular receptors. However, low protein concentrations, genetic variation, biochemical modification, and proteolytic breakdown can induce decomposition of multimeric SP-D into low-molecular weight forms, which may induce pro-inflammatory SP-D signaling. Multimeric SP-D can decompose into trimeric SP-D, and this process, and total SP-D levels, are partly determined by variation within the SP-D gene, SFTPD. SP-D has been implicated in the development of respiratory diseases including respiratory distress syndrome, bronchopulmonary dysplasia, allergic asthma, and chronic obstructive pulmonary disease. Disease-induced breakdown or modifications of SP-D facilitate its systemic leakage from the lung, and circulatory SP-D is a promising biomarker for lung injury. Moreover, studies in preclinical animal models have demonstrated that local pulmonary treatment with recombinant SP-D is beneficial in these diseases. In recent years, SP-D has been shown to exert antimicrobial and anti-inflammatory effects in various non-pulmonary organs and to have effects on lipid metabolism and pro-inflammatory effects in vessel walls, which enhance the risk of atherosclerosis. A common SFTPD polymorphism is associated with atherosclerosis and diabetes, and SP-D has been associated with metabolic disorders because of its effects in the endothelium and adipocytes and its obesity-dampening properties. This review summarizes and discusses the reported genetic associations of SP-D with disease and the clinical utility of circulating SP-D for respiratory disease prognosis. Moreover, basic research on the mechanistic links between SP-D and respiratory, cardiovascular, and metabolic diseases is summarized. Perspectives on the development of SP-D therapy are addressed.
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