title: Hyaluronan ameliorates LPS-induced acute lung injury in mice via Toll-like receptor (TLR) 4-dependent signaling pathways.
abstract: Toll-like receptor-4 (TLR4) signaling has been implicated in innate immunity and acute inflammation following acute lung injury (ALI). As such, modulating inflammatory response through TLR4 represents an attractive therapeutic approach to treat ALI. Increasing evidence demonstrates that hyaluronan (HA) can modulate TLR4 activation and has shown early promise as a therapeutic agent in ALI. However, the mechanism associated with HA has not been fully elucidated. In the current study, we sought to determine the effects of HA on lipopolysaccharide (LPS)-induced inflammatory response and gain insights into the mechanism of action in mice with intratracheal instillation of LPS. Our results demonstrate that in contrast to mice challenged with LPS, pretreatment with HA significantly inhibited inflammatory cell recruitment, attenuated lung injury and suppressed the level of cytokine/chemokine in bronchial alveolar lavage fluid (BALF). Investigation of the mechanism responsible for inhibition of LPS activation showed HA treatment significantly inhibited the nuclear translocation of NF-κB p65 and protein expression of myeloid differentiation primary response protein (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) and p38 MAPK, JNK and ERK activation in lung tissue. Furthermore, we compared the protection effect of HA in TLR4-deficient mice with those of genetically matched wild type (WT) mice in an acute model of lung injury. However, in TLR4-deficient mice, HA pretreatment before LPS instillation fail to affect the LPS response. Therefore, our findings suggest that HA pretreatment attenuated LPS-induced ALI and the anti-inflammatory function of HA was partial dependent on TLR4, which shed new light on potential elements that regulate the lung injury response.
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Changqing
authors: C
authors: Xu
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Gang
authors: G
authors: Chen
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Weiwei
authors: W
authors: Yang
authors: Department of Integrative Medicine, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China.
authors: Yizhe
authors: Y
authors: Xu
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Yongfang
authors: Y
authors: Xu
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Xuqing
authors: X
authors: Huang
authors: Maternal and Child Health Hospital Affiliated to Zhejiang University, Hangzhou 311121, China.
authors: Jiangang
authors: J
authors: Liu
authors: Department of Respiration, Affiliated Hospital, School of Medicine, Hangzhou Normal University, 16 Wen Zhou Road, Hangzhou 311121, China.
authors: Yuejuan
authors: Y
authors: Feng
authors: Department of Physiology and Pharmacology, West Virginia University, WV 26506, USA.
authors: Yanchun
authors: Y
authors: Xu
authors: Department of Integrative Medicine, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China. Electronic address: lbj825@163.com.
authors: Baojun
authors: B
authors: Liu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid
keywords: Acute lung injury; Hyaluronan; Inflammation; LPS; Toll-like receptor-4