title: Inhibition of HA synthase 3 mRNA expression, with a phosphodiesterase 3 inhibitor, blocks lung injury in a septic ventilated rat model.
abstract: Low-molecular-weight hyaluronan produced by hyaluronan synthase 3 (HAS3) has been shown to play a role in acute lung injury secondary to high-tidal-volume ventilation. Phosphodiesterase 3 inhibitors have been shown to decrease HAS3 expression. We hypothesized that low-molecular-weight hyaluronan (LMW HA) produced by HAS3 mediates LPS-induced lung injury in the mechanically ventilated rat and that milrinone (MIL), by blocking HAS3 mRNA expression, would prevent the injury. Rats were randomized to four groups: controls with mechanical ventilation at 7 cc/kg MV, MV+LPS, MV+MIL, and MV+LPS+MIL. Rats were intubated and ventilated without PEEP for 4 h. Lipopolysaccharide (LPS) (1 mg/kg) was infused into the arterial line 1 h prior to MV. MIL 10 microg/kg/min (or an equivalent volume of saline) was infused through the venous line at the beginning of MV. Bronchoalveolar lavage fluid (BAL) was collected after 4 h of ventilation and lungs were saved for histopathology. LPS significantly increased neutrophil infiltration and protein concentration in the BAL and augmented lung injury score on histology. MIL significantly lowered alveolar protein and neutrophil infiltration as well as lung injury in response to LPS. Furthermore, MIL decreased the mRNA expression for HAS3 and MIP2 in lung tissue and decreased the protein content in BAL. MIL, a commonly used inotropic agent, inhibited LPS-induced lung inflammation and lung injury in mechanically ventilated rats. The anti-inflammatory properties of MIL may be mediated by inhibition of HAS3 and/or MIP2 and could be beneficial in the treatment of sepsis.
authors: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA. hmrabat@partners.org
authors: Hicham
authors: H
authors: Mrabat
authors: John
authors: J
authors: Beagle
authors: Zhao
authors: Z
authors: Hang
authors: Hari G
authors: HG
authors: Garg
authors: Charles A
authors: CA
authors: Hales
authors: Deborah A
authors: DA
authors: Quinn
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
chemical_list: D000893:Anti-Inflammatory Agents; D054426:Chemokine CXCL2; D008070:Lipopolysaccharides; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491355:Has3 protein, rat; D000076002:Hyaluronan Synthases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone