Anti-CCL2 therapy reduces oxygen toxicity to the immature lung.

Oxygen toxicity constitutes a key contributor to bronchopulmonary dysplasia (BPD). Critical step in the pathogenesis of BPD is the inflammatory response in the immature lung with the release of pro-inflammatory cytokines and the influx of innate immune cells. Identification of efficient therapies to alleviate the inflammatory response remains an unmet research priority. First, we studied macrophage and neutrophil profiles in tracheal aspirates of n = 103 preterm infants <29 weeks´ gestation requiring mechanical ventilation. While no differences were present at birth, a higher fraction of macrophages, the predominance of the CD14+CD16+ subtype on day 5 of life was associated with moderate/severe BPD. Newborn CCL-2-/- mice insufficient in pulmonary macrophage recruitment had a reduced influx of neutrophils, lower apoptosis induction in the pulmonary tissue and better-preserved lung morphometry with higher counts of type II cells, mesenchymal stem cells and vascular endothelial cells when exposed to hyperoxia for 7 days. To study the benefit of a targeted approach to prevent the pulmonary influx of macrophages, wildtype mice were repeatedly treated with CCL-2 blocking antibodies while exposed to hyperoxia for 7 days. Congruent with the results in CCL-2-/- animals, the therapeutic intervention reduced the pulmonary inflammatory response, attenuated cell death in the lung tissue and better-preserved lung morphometry. Overall, our preclinical and clinical datasets document the predominant role of macrophage recruitment to the pathogenesis of BPD and establish the abrogation of CCL-2 function as novel approach to protect the immature lung from hyperoxic injury.

Effects of stomach inflation on haemodynamic and pulmonary function during spontaneous circulation in pigs.

AIM: Stomach inflation during mask ventilation is frequent, but the effects on haemodynamic and pulmonary function are unclear. We evaluated the effects of stomach inflation on haemodynamic and pulmonary function during spontaneous circulation in a porcine model. METHODS: Randomised prospective animal study. After randomisation, in 23 domestic pigs the stomach was inflated every 90s with 0L (control; n=8), 0.5L (n=7) or 1L (n=8) ambient air. RESULTS: After 22.5min, i.e. 8.5L in the 0.5L and 17L in the 1L stomach inflation group, stomach inflation increased central venous pressure (median) (control: 10mmHg vs. 1L: 23mmHg, P<0.05) and mean pulmonary artery pressure (control: 24mmHg vs. 1L: 45mmHg, P<0.05). As a result stroke volume index decreased (control: 135mL/kg vs. 0.5L: 90mL/kg, P<0.05; vs. 1L: 72mL/kg, P<0.05). Stomach inflation also decreased static pulmonary compliance (control: 24mL/cmH(2)O vs. 0.5L: 8mL/cmH(2)O, P<0.05; vs. 1L: 3mL/cmH(2)O, P<0.05), which increased peak airway pressure (control: 28cmH(2)O vs. 0.5L: 69cmH(2)O, P<0.05; vs. 1L: 73cmH(2)O, P<0.05). Additionally, arterial oxygen partial pressure (control: 305mmHg vs. 0.5L: 140mmHg, P<0.05; vs. 1L: 21mmHg, P<0.05) and systemic oxygen delivery (control: 53mLO(2)/min vs. 1L: 19mLO(2)/min, P<0.05) decreased. Stomach inflation increased mortality (control: 0/8 vs. 1L: 5/8, P<0.05). CONCLUSIONS: Stomach inflation with 1L when compared to 0.5L increments resulted in faster haemodynamic and pulmonary failure and increased mortality. Stomach inflation may cause a hyper-acute abdominal compartment syndrome.

Arginine vasopressin does not alter mucosal tissue oxygen tension and oxygen supply in an acute endotoxemic pig model.

OBJECTIVE: To determine the effects of increasing dosages of continuously infused arginine-vasopressin (AVP) on mucosal tissue oxygen tension and oxygen supply in an auto-perfused, innervated jejunal segment in an acute endotoxic porcine model. DESIGN: Prospective, randomized, experimental study. SETTING: University hospital animal research laboratory. INTERVENTIONS: Jejunal mucosal tissue PO2 was measured employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Systemic hemodynamic variables, mesenteric-venous and systemic acid base and blood gas variables and lactate measurements were recorded. Measurements were performed at baseline, after E. coli lipopolysaccharide (LPS) administration and at 20 min intervals during incremental AVP infusion (n=8; 0.014, 0.029, 0.057, 0.114 and 0.229 IU kg(-1) h(-1), respectively) or infusion of saline (n =8). MEASUREMENTS AND RESULTS: LPS infusion leads to a significant (P<0.05) decrease of mucosal tissue oxygen tension (PO2muc, 24+/-3 to 12+/-2 mmHg) and microvascular hemoglobin oxygen saturation (HbO2, 38+/-4 to 21+/-4%). Mesenteric venous lactate level increased (2.4+/-0.3 to 4.7+/-1.7 mmol l(-1)), while mesenteric venous pH decreased (7.38+/-0.02 to 7.26+/-0.12), indicating tissue hypoxia. AVP significantly increased mean arterial pressure (MAP, 81+/-15 to 97+/-17 at 0.057 IU kg(-1) h(-1)). No differences in jejunal mucosal oxygenation occurred between study groups at any dosage during the experimental protocol. CONCLUSION: AVP administration did not further compromise mucosal tissue oxygen tension and oxygen supply in the acute phase of endotoxic pigs.