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BIOLOGICAL EFFECTS OF CORTICOSTEROIDS ON PNEUMOCOCCAL PNEUMONIA IN MICE AND HUMANS

ABSTRACT: Rationale: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia. Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, but the mechanisms of this benefit remain unclear. Objectives: To investigate the biologic effects of corticosteroids in pneumococcal pneumonia in mice and in patients Methods: We studied lower respiratory tract transcriptomes from an observational cohort of mechanically ventilated patients and from a pneumonia model in mice. We also carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify mechanisms of lung injury in S. pneumoniae with and without adjunctive steroid therapy. Measurement and Main Results: Transcriptomic analysis identified pleiotropic effects of steroid therapy on the lower respiratory tract in critically ill patients with pneumococcal pneumonia, findings that were reproducible in mice. In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathology lung injury score, and (5) hypoxemia, but did not increase bacterial burden. Conclusions: In combination with appropriate antibiotics in mice, treatment of pneumococcal pneumonia with steroid therapy reduces hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The concordance of transcriptional data in the mouse model and in patients with pneumococcal pneumonia supports the translational relevance of this work.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246398 | GEO | 2024/06/05

REPOSITORIES: GEO

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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.

Project description:Rationale: Using an ortholog candidate gene approach, we previously identified GADD45a (growth arrest and DNA damage-inducible gene 45a) as a potential novel candidate involved in ventilator-induced lung injury (VILI). Objectives: We investigated whether genetically engineered mice with GADD45a deletion were more susceptible to ventilator- or endotoxin (LPS)-induced lung injury. We employed genomic strategies to explore the mechanistic involvement of GADD45a in inflammatory lung injury. Methods: Wild-type C57Bl/6 and GADD45a-/- mice were phenotyped for lung injury following exposure to high tidal volume ventilation (VILI) or intratracheal LPS. Whole lung homogenates were utilized for gene expression studies of ventilated animals and spontaneously breathing controls. To explore the consequences of GADD45a depletion on lung vascular permeability, electrical resistance was measured using human endothelial cells (EC) transfected with small interfering RNA (siRNA) specific for GADD45a or control sequence, or with active Akt1/PKBï¡ cDNA. Results: Mice harboring deletion of GADD45a were modestly susceptible to LPS-induced injury and profoundly susceptible to VILI, demonstrating increased inflammation and increased microvascular permeability. VILI-exposed GADD45a-/- mice manifested striking neutrophilic alveolitis and increased levels of BAL protein, IgG, and inflammatory cytokines. Expression profiling revealed strong dysregulation in the B cell receptor signaling pathway in GADD45a-/- mice, with involvement of several PI3K/Akt signaling components. Akt protein and phospho-Akt were reduced in GADD45a-/- lungs. Further, human EC with reduced GADD45a (siRNA) exhibited potentiated LPS-induced barrier dysfunction, which was attenuated by overexpressing active Akt1. Conclusions: GADD45a, which modulates Akt availability, is a significant participant in modulating vascular permeability and susceptibility to VILI. Experiment Overall Design: 4 experimental groups, each with 3 mouses. Wild type control group, VILI group, GADD-/- group, GADD-/- and VILI group.

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BIOLOGICAL EFFECTS OF CORTICOSTEROIDS ON PNEUMOCOCCAL PNEUMONIA IN MICE AND HUMANS

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