Partially-desulfated heparin improves survival inPseudomonaspneumonia by enhancing bacterial clearance and ameliorating lung injury

Abstract

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.

Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding

“…Furthermore, the addition of dp4 or dp10 heparin to TAK242-treated cells provided no additional suppression of TNFα expression, suggesting that dp4 and dp10 inhibited low-dose CTH-mediated endothelial activation via a similar mechanisms of TLR4 antagonism. This inhibitory effect is consistent with a previous report suggesting that N -sulfated HS fragments can prevent HMGB1-mediated activation of TLR4 (16). However, highly-sulfated HS oligosaccharides (as modeled by dp4 and dp10 heparin) had no effect on lipopolysaccharide (LPS)-induced TNFα expression (Fig 7d), suggesting that these oligosaccharides are not simply pan-TLR4 inhibitors, but may have specificity for histone- (or HMGB1-) activation of this pattern receptor.…”

HMGB1 in health and disease

“…Community-acquired pneumonia is pneumonia acquired infectiously from normal social contact, as opposed to being acquired during hospitalization (termed hospital-acquired pneumonia). Increased serum HMGB1 level is caused by bacteria or virus in both community-acquired and hospital-acquired pneumonia (Achouiti et al, 2013; Angus et al, 2007; Entezari et al, 2012; Ito et al, 2011; Kosai et al, 2008; Sharma et al, 2013; Tasaka et al, 2010; van Zoelen et al, 2008; Zhou et al, 2011d). Both RAGE and TLR4 play roles in the regulation of HMGB1-mediated inflammatory response during pneumonia (Achouiti et al, 2013; Entezari et al, 2012; Ramsgaard et al, 2011).…”

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…Systemic treatment with anti-HMGB1 mAb in a preclinical cystic fibrosis model conferred significant protection against P. aeruginosa-induced neutrophil recruitment, protein leak, and lung injury (Entezari et al 2012). Treatment with partially desulfated heparin in preclinical models of pneumonia reduced airway HMGB1 levels and neutrophilic lung injury (Griffin et al 2014;Sharma et al 2014). Desulfated heparins are derivatives with anti-inflammatory properties but minimal anti-coagulatory effects.…”