Abstract
The assessment of systemic corticosteroid effects on intrapulmonary disease biomarkers is challenging. This retrospective evaluation of a human endotoxemia model quantified ACE2 and fibrin degradation product (FDP) concentrations in bronchoalveolar lavage fluid (BALF) samples from a randomized, double-blind, placebo-controlled study (NCT01714427). Twenty-four healthy volunteers received either 2 × 40 mg intravenous dexamethasone or placebo. These doses were administered 12 h apart prior to bronchoscopy-guided intrabronchial lipopolysaccharide (LPS) stimulation (control: saline into the contralateral lung segment). We quantified ACE2 concentration, the Angiotensin-II-to-Angiotensin-1-7 conversion rate as well as FDP in BALF 6 h after LPS instillation. In placebo-treated subjects, LPS instillation increased ACE2 concentrations compared to unstimulated lung segments [1,481 (IQR: 736–1,965) vs. 546 (413–988) pg/mL; p = 0.016]. Dexamethasone abolished the increase in ACE2 concentrations (p=0.13). Accordingly, LPS instillation increased the Angiotensin-II-to-Angiotensin-1-7 conversion capacity significantly in the placebo cohort, indicating increased enzymatic activity (p = 0.012). FDP increased following LPS-instillation [8.9 (2.7–12.2) vs. 6.6 (0.9–9.6) ng/mL, p = 0.025] in the placebo group, while dexamethasone caused a shut-down of fibrinolysis in both lung segments. LPS instillation increased ACE2 concentration, its enzymatic activity and FDP, which was mitigated by systemic dexamethasone treatment. Our results strengthen previously published findings regarding the efficiency of corticosteroids for the treatment of COVID-19-induced acute lung injury.
Highlights
Corticosteroids are widely used as an anti-inflammatory treatment in lung disease and have emerged as an effective treatment strategy in severe Corona Virus Disease 2019 (COVID19) (1)
We hypothesized that bronchial LPS instillation increases pulmonary Angiotensin Converting Enzyme 2 (ACE2) and fibrin degradation product (FDP) concentrations, which may be mitigated by systemic dexamethasone treatment
We found an increased capacity of Angiotensin-II-to-Angiotensin-1-7 conversion capacity in bronchoalveolar lavage fluid (BALF) from LPS stimulated lung segments in patients receiving placebo: In unstimulated lung segments the median ACE2-dependent Ang[1-7] production capacity was at the lower level of quantification (LLOQ), while following LPS stimulation Angiotensin [1-7] production capacity increased to 26 (22–55) ng/mL/h, p = 0.012 (Figure 2)
Summary
Corticosteroids are widely used as an anti-inflammatory treatment in lung disease and have emerged as an effective treatment strategy in severe Corona Virus Disease 2019 (COVID19) (1). It was subsequently hypothesized that downregulation of ACE2 may disturb the pulmonary and possibly the systemic RAAS, resulting in a certain form of severe lung injury compatible with COVID19. This pathophysiological concept, is primarily based on murine models. We observed increased systemic ACE2 concentrations in patients with severe COVID-19 that were associated with elevated Interleukin-6 (IL-6) levels (9). It is well-established that inflammation activates coagulation and fibrinolysis in bacterial pneumonia, the latter primarily mediated by tumor necrosis factor alpha (TNF-α) (10). We hypothesized that bronchial LPS instillation increases pulmonary ACE2 and FDP concentrations, which may be mitigated by systemic dexamethasone treatment
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