Nosocomial pneumonia (NP, or
hospital-acquired pneumonia) is associated with
infections originating from hospital-borne pathogens. Persistent microbial presence and
acute lung injury are common features of these
infections, contributing to the high mortality rates and excessive financial burden for these patients. Pseudomonas aeruginosa (PA), a gram-negative opportunistic pathogen, is one of the prominent pathogens associated with NP. PA
pneumonia is characterized by excessive secretion of inflammatory
cytokines, neutrophil infiltration, and subsequent lung damage. The persistent presence of PA along with overwhelming inflammatory response is suggestive of impairment in innate immunity. High mobility group box 1 (
HMGB1), a recently discovered potent pro-inflammatory
cytokine, plays an important role in PA lung
infections by compromising innate immunity via impairing phagocyte function through
toll-like receptors (TLR) TLR2 and TLR4. ODSH (2-O, 3-O-desulfated heparin), a
heparin derivative with significant anti-inflammatory properties but minimal anti-coagulatory effects, has been shown to reduce neutrophilic
lung injury in the absence of active microbial
infections. This study examined the effects of ODSH on PA
pneumonia. This study demonstrates that ODSH not only reduced PA-induced
lung injury, but also significantly increased bacterial clearance. The ameliorated
lung injury, together with the increased bacterial clearance, resulted in marked improvement in the survival of these animals. The resulting attenuation in
lung injury and improvement in bacterial clearance were associated with decreased levels of airway
HMGB1. Furthermore, binding of
HMGB1 to its receptors TLR2 and TLR4 was blunted in the presence of ODSH. These data suggest that ODSH provides a potential novel approach in the adjunctive treatment of PA
pneumonia.