Perinatal maternal antibiotic exposure augments lung injury in offspring in experimental bronchopulmonary dysplasia

Copyright © 2020 the American Physiological Society. During the newborn period, intestinal commensal bacteria influence pulmonary mucosal immunology via the gut-lung axis. Epidemiological studies have linked perinatal antibiotic exposure in human newborns to an increased risk for bronchopulmonary dysplasia, but whether this effect is mediated by the gut-lung axis is unknown. To explore antibiotic disruption of the newborn gut-lung axis, we studied how perinatal maternal antibiotic exposure influenced lung injury in a hyperoxia-based mouse model of bronchopulmonary dysplasia. We report that disruption of intestinal commensal colonization during the perinatal period promotes a more severe bronchopulmonary dysplasia phenotype characterized by increased mortality and pulmonary fibrosis. Mechanistically, metagenomic shifts were associated with decreased IL-22 expression in bronchoalveolar lavage and were independent of hyperoxia-induced inflammasome activation. Collectively, these results demonstrate a previously unrecognized influence of the gut-lung axis during the development of neonatal lung injury, which could be leveraged to ameliorate the most severe and persistent pulmonary complication of preterm birth

Combination therapy with ampicillin and azithromycin improved outcomes in a mouse model of group B streptococcal sepsis.

Evidence suggests that β-lactam monotherapy of streptococcal infections may incite stronger inflammation and is inferior to combination therapy with macrolides. We hypothesized that use of macrolides alone or in combination with a β-lactam for group B streptococcal (GBS) sepsis would improve outcomes by reducing inflammation.TNF-α was measured from supernatants of RAW 264.7 cells stimulated with GBS isolates, in presence of four treatment regimens: ampicillin alone, azithromycin alone, or combination of azithromycin plus ampicillin. Mouse model of GBS sepsis was developed and treated with same four regimens. Clinical sepsis scores were monitored; serum cytokines (TNF-α, IL-6, IL-10) and chemokines (MIP-1α) were measured at the end.GBS isolates exposed to azithromycin or combination (compared to ampicillin alone) stimulated less TNF production in vitro. In the murine sepsis model, mortality was lower along with decreased sepsis scores in mice treated with combination therapy. Mean serum IL-6 was lower in mice treated with azithromycin alone (66±52 pg/ml) or combination of ampicillin plus azithromycin (52±22 pg/ml) compared to ampicillin alone (260±160 pg/ml) (p<0.005).Combination therapy of ampicillin+azithromycin improved outcomes in a murine GBS sepsis model; this therapeutic approach deserves additional study

Efficacy of Sildenafil in Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is a common comorbidity in infants with bronchopulmonary dysplasia (BPD). Sildenafil is a widely recognized therapy for PH, but its efficacy in infants with BPD is questionable. We propose to assess the efficacy of sildenafil in BPD-associated PH as evaluated based on transthoracic echocardiography (TTE) changes and clinical measures. Methods: Data were retrospectively and prospectively collected. Inclusion criteria were gestational age (GA) Results: In total, 19 patients were enrolled in the study, having a median GA of 24 3/7 weeks (IQR 23 5/7–25 5/7) and a median BW of 598 g (IQR 572–735). Sildenafil treatment was started at a median PMA of 40.4 weeks. The median respiratory severity score (RSS) at 28 d was 6.5, RSS and FiO2 showed improvement about 12 weeks after starting sildenafil treatment. Conclusions: Improvement in PH was noted via TTE, and patients had improvement in their RSS and FiO2 after prolonged therapy. However, TTE improvements did not correlate with clinical improvements

Clinical sepsis score in GBS infected mice treated with antibiotics.

<p>Mean clinical sepsis score of GBS infected mice in each group was calculated and plotted as shown. * = p ≤0.01.</p

TNF-α levels in GBS infected mice treated with antibiotics.

<p>Mean serum TNF-α levels were measured and shown among GBS infected mice treated with antibiotics. * = p<0.01.</p

Survival analysis of GBS infected mice treated with antibiotics.

<p>Kaplan- Meier survival graph shows that mortality was higher in GBS infected mice treated with ampicillin alone (AMP) compared to azithromycin alone (AZM) or in combination with ampicillin and azithromycin (AMP+AZM).</p

Azithromycin resistant GBS mediated murine macrophages secreted lower TNF-α with AMP+AZM compared to AMP alone.

<p>Mean± SD TNF production (pg/mL) by RAW 264.7 cells in response to stimulation with 10 ⁶ cfu/mL of azithromycin resistant GBS, when treated with ampicillin alone at (20mg/L), azithromycin alone at (5mg/L and 20mg/L) and combination antibiotics ampicillin (20mg/L) and azithromycin (20mg/L) is shown. * = p ≤0.01.</p

Clinical sepsis score in AZM resistant GBS infected mice treated with antibiotics.

<p>Mean clinical sepsis score of GBS infected mice in each group was calculated and plotted as shown. * = p ≤0.01.</p

GBS Ia mediated murine macrophages secreted lower TNF-α with AMP+AZM compared to AMP alone.

<p>Mean TNF production (pg/mL) ± SD by RAW 264.7 cells in response to stimulation with 10⁶ cfu/mL of GBS Ia, when treated with ampicillin alone at(20mg/L), azithromycin (AZM) alone at (5mg/L and 20mg/L) and combination antibiotics ampicillin (20mg/L) and azithromycin (20mg/L) is shown. * = p ≤0.01.</p