High-molecular-weight hyaluronan--a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats.
BACKGROUND
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 TNFalpha 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.
Liu
Yung-Yang
YY
Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114, USA.
Lee
Cheng-Hung
CH
Dedaj
Rejmon
R
Zhao
Hang
H
Mrabat
Hicham
H
Sheidlin
Aviva
A
Syrkina
Olga
O
Huang
Pei-Ming
PM
Garg
Hari G
HG
Hales
Charles A
CA
Quinn
Deborah A
DA
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006820:Hyaluronic Acid / Q000737:chemistry / Q000627:therapeutic use*; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D006820:Hyaluronic Acid