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High-molecular-weight hyaluronan – a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats

Yung-Yang Liu3,4,1,2, Cheng-Hung Lee1,2,5, Rejmon Dedaj1,2, Hang Zhao1,2, Hicham Mrabat1,2, Aviva Sheidlin6, Olga Syrkina1,2,7, Pei-Ming Huang1,2,8, Hari G Garg1,2, Charles A Hales1,2 and Deborah A Quinn1,2*

Author Affiliations

1 Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114, USA

2 Harvard Medical School, 25 Shattuck St, Boston, MA, 02115 USA

3 Chest Department, Taipei Veterans General Hospital, Sec 2, Shih-Pai Rd, Taipei, 11217, Taipei, Taiwan

4 National Yang-Ming University, School of Medicine, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan

5 Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan, 70428 Taiwan

6 Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142 USA

7 Shriners Burn Hospital, 51 Blossom Street, Boston, MA 02114 USA

8 Department of Traumatology and Surgery, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei 100, Taiwan

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Critical Care 2008, 12:R102 doi:10.1186/cc6982

Published: 8 August 2008

Abstract

Introduction

Mechanical ventilation with even moderate-sized tidal volumes synergistically increases lung injury in sepsis and has been associated with proinflammatory low-molecular-weight hyaluronan production. High-molecular-weight hyaluronan (HMW HA), in contrast, has been found to be anti-inflammatory. We hypothesized that HMW HA would inhibit lung injury associated with sepsis and mechanical ventilation.

Methods

Sprague–Dawley rats were randomly divided into four groups: nonventilated control rats; mechanical ventilation plus lipopolysaccharide (LPS) infusion as a model of sepsis; mechanical ventilation plus LPS with HMW HA (1,600 kDa) pretreatment; and mechanical ventilation plus LPS with low-molecular-weight hyaluronan (35 kDa) pretreatment. Rats were mechanically ventilated with low (7 ml/kg) tidal volumes. LPS (1 or 3 mg/kg) or normal saline was infused 1 hour prior to mechanical ventilation. Animals received HMW HA or low-molecular-weight hyaluronan via the intraperitoneal route 18 hours prior to the study or received HMW HA (0.025%, 0.05% or 0.1%) intravenously 1 hour after injection of LPS. After 4 hours of ventilation, animals were sacrificed and the lung neutrophil and monocyte infiltration, the cytokine production, and the lung pathology score were measured.

Results

LPS induced lung neutrophil infiltration, macrophage inflammatory protein-2 and TNFα mRNA and protein, which were decreased in the presence of both 1,600 kDa and 35 kDa hyaluronan pretreatment. Only 1,600 kDa hyaluronan completely blocked both monocyte and neutrophil infiltration and decreased the lung injury. When infused intravenously 1 hour after LPS, 1,600 kDa hyaluronan inhibited lung neutrophil infiltration, macrophage inflammatory protein-2 mRNA expression and lung injury in a dose-dependent manner. The beneficial effects of hyaluronan were partially dependent on the positive charge of the compound.

Conclusions

HMW HA may prove to be an effective treatment strategy for sepsis-induced lung injury with mechanical ventilation.