Martin Chada

Aerosolized adrenomedullin suppresses pulmonary transforming growth factor-β1 and interleukin-1β gene expression in vivo

The effect of aerosolized adrenomedullin on interleukin-1β and transforming growth factor (TGF)-β1 mRNA and protein expression was studied in surfactant depleted piglets, receiving aerosolized adrenomedullin (adrenomedullin, n=6), aerosolized adrenomedullin plus i.v. NG-nitro-l-arginine-methylester (adrenomedullin+l-NAME, n=5), or aerosolized saline solution (control, n=6). After 8 h of aerosol interval therapy, mRNA expression of interleukin-1β and TGF-β1 in lung tissue was quantified normalized to β-actin and hypoxanthine-guanine-phosphoribosyl-transferase by real-time polymerase chain reaction (PCR). Interleukin-1β and TGF-β1 protein concentration in lung tissue was quantified by enzyme-linked immunosorbent assay (ELISA). In the adrenomedullin group, interleukin-1β and TGF-β1 mRNA expression was lower than in controls. Reduction for interleukin-1β/β-actin was 56% (p<0.001), for interleukin-1β/hypoxanthine-guanine-phosphoribosyl-transferase 60% (p<0.001), for TGF-β1/β-actin 65.5% (p<0.001), and for TGF-β1/hypoxanthine-guanine-phosphoribosyl-transferase 56.2% (p<0.001). Mean interleukin-1β protein expression was different between the groups, p<0.05 (adrenomedullin 601±61, Control 836±88 pg/mg protein). l-NAME did not antagonize adrenomedullin effect on TGF-β1 mRNA. In conclusion, aerosolized adrenomedullin reduced pulmonary inflammatory and pro-fibrotic response.

Brief adrenomedullin inhalation leads to sustained reduction of pulmonary artery pressure

The effect of aerosolised adrenomedullin (ADM), a potent vasodilator peptide, on pulmonary artery pressure was studied for 24 h in a surfactant-depleted piglet model. Animals received either aerosolised ADM (50 ng·kg−1·min−1, ADM, n=6), or aerosolised normal saline solution (control, n=6). Aerosol therapy was performed for a 2 h treatment period followed by a 22 h observation period. Ventilator settings were adapted to keep arterial oxygen tension and carbon dioxide arterial tension between 13.3–14.6 kPa and 4.9–5.7 kPa, respectively. Aerosolised ADM reduced mean pulmonary artery pressure (MPAP) compared with the control group (end-point median 24 h after therapy start: ΔMPAP −14.0 versus −8.0 mmHg; 23.5 h after therapy start). After therapy start, mean systemic arterial pressure (MAP) was not significantly different between the groups (end-point median: MAP ADM 70 (61/74) versus control 72 (54/81) mmHg). Endothelin-1, a potent pulmonary vasoconstrictor, is regulated by ADM via cAMP. Twenty two hours after inhalation of aerosolised ADM, endothelin-1 mRNA in lung tissue and endothelin-1 protein expression in pulmonary arteries was reduced compared with controls (median semi-quantitative immunhistochemical score: ADM 0.21, control 0.76). Aerosolised adrenomedullin significantly reduced mean pulmonary artery pressure independently of arterial oxygen tension.

Dose response to aerosolized perflubron in a neonatal swine model of lung injury.

Aerosolized perfluorocarbon (PFC) improves gas exchange, lung mechanics, and pulmonary artery pressure. The objective of this intervention was to study the dose-response effect to aerosolized perfluorooctylbromide (PFOB; perflubron, LiquiVent, Alliance Pharmaceutical Corp.) in surfactant-depleted piglets. After induction of lung injury by saline lavage, 25 newborn piglets were randomly assigned to receive 0, 1.25, 2.5, 5.0, or 7.5 mL/kg aerosolized PFOB per hour. A 2-h therapy period was followed by a 3-h observation period. In all animals, respiratory support was performed with intermittent mandatory ventilation. After aerosol treatment and 3 h of observation, arterial oxygen pressure was similarly improved in the 2.5-, 5.0-, and 7.5-mL·kg−1·h−1 aerosol-PFOB groups and higher compared with the 1.25-mL·kg−1·h−1 aerosol-PFOB (P < 0.01) and the control groups (P < 0.001). Compared with the control group, arterial carbon dioxide pressure was significantly reduced with 2.5-, 5.0-, and 7.5-mL·kg−1·h−1 aerosol-PFOB (P < 0.001). Treatment with 1.25 mL·kg−1·h−1 aerosol-PFOB did not significantly affect arterial carbon dioxide pressure. The 20% terminal dynamic compliance/dynamic compliance was significantly improved in the groups that received 2.5, 5.0, and 7.5 mL·kg−1·h−1 aerosol-PFOB compared with control animals. Mean pulmonary artery pressure was lower after therapy with 5.0 and 7.5 mL·kg−1·h−1 aerosol-PFOB (P < 0.01) than in the control group. IL-1β gene expression in lung tissue was significantly reduced with PFOB 1.25 mL·kg−1·h−1. In summary, aerosolized PFOB improved terminal dynamic compliance, pulmonary gas exchange, and pulmonary artery pressure in a dose-dependent manner. In terms of oxygenation and lung mechanics, the optimum dose was between 2.5 and 5 mL·kg−1·h−1.

Anakinra (IL-1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model.

In acute respiratory distress syndrome (ARDS) with pulmonary hypertension, interleukin‐1β (IL‐1β) and interleukin‐8 (IL‐8) are involved in the pulmonary inflammatory reaction. The purpose of this study was to determine whether systemic and aerosolized administered IL‐1 receptor antagonist (IL‐1Ra) Anakinra (Kineret™) improves lung mechanics and pulmonary artery pressure in surfactant depleted newborn piglets. After induction of acute lung injury by lung lavage, neonatal piglets received repetitive treatment of either aerosolized IL‐1Ra (IL‐1Ra‐Aerosol) or intravenous IL‐1Ra (IL‐1Ra‐i.v.), or saline solution as control. IL‐1Ra given as aerosol or intravenously significantly reduced mean pulmonary artery pressure (MPAP) but did not influence mean systemic arterial pressure (MAP) compared with the control group. IL‐1β and IL‐8 mRNA expressions normalized to β‐actin and hypoxanthine‐guanine‐phosphoribosyl transferase were significantly reduced in the IL‐1Ra‐Aerosol group but not in IL‐1Ra‐i.v. group compared to the control group. The lung injury score was not significantly different between IL‐1Ra groups and the control group. Application of aerosolized IL‐1Ra reduced MPAP without affecting MAP in a piglet model of surfactant depletion with pulmonary hypertension. Furthermore, there is evidence for reduction of early pro‐inflammatory pulmonary reaction. Pediatr Pulmonol. 2008; 43:851–857.

Parecoxib does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis.

Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity.

Diffuse Encephalopathy Associated with Isolated Cerebral Langerhans Cell Histiocytosis

BACKGROUND Langerhans cell histiocytosis is a rare disease of the monocyte-macrophage system. Abnormalities of the hypothalamic-pituitary region are common in individuals with central nervous system involvement. PATIENT DESCRIPTION This six-year-old boy developed rapidly progressive aggressive behavior, central diabetes insipidus, and repeated complex partial seizures. Magnetic resonance imaging revealed a diffuse leukoencephalopathy-like pattern and numerous infratentorial and supratentorial granulomatous nodules in the brain parenchyma along with infundibular and hypothalamic mass lesions. Stereotactic serial biopsies enabled histopathologic and immunohistochemical diagnosis of Langerhans cell histiocytosis. CONCLUSIONS Similar MRI findings have rarely been described in the literature. These findings represent part of the broad neuroradiological spectrum of Langerhans cell histiocytosis of the nervous system in children.