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Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE186705 | GEO | 2021/12/07

REPOSITORIES: GEO

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Project description:Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page <a href="study.cgi?study_id=phs000631">phs000631</a> ARDSnet iSPAAR Consortium. <ul> <li><a href="study.cgi?study_id=phs000334">phs000334</a> ESP_LungGO_ALI </li> <li><a href="study.cgi?study_id=phs000686">phs000686</a> ALI_GeneticRisk </li> </ul>

Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

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Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome

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