Title: Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier.
Authors: Zhou, Ting; Yu, Zhihong; Jian, Ming-Yuan; Ahmad, Israr; Trempus, Carol; Wagener, Brant M; Pittet, Jean-Francois; Aggarwal, Saurabh; Garantziotis, Stavros; Song, Weifeng; Matalon, Sadis
Published In Am J Physiol Lung Cell Mol Physiol, (2018 05 01)
Abstract: Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO-/-) mice, and CD44 gene-deficient (CD44-/-) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44-/- resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO-/- mice. Isolated perfused lungs of HCl instilled WT but not of CD44-/- mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.
PubMed ID: 29368549
MeSH Terms: Acute Lung Injury/chemically induced; Acute Lung Injury/drug therapy*; Acute Lung Injury/metabolism; Acute Lung Injury/pathology; Animals; Blood-Air Barrier/drug effects*; Blood-Air Barrier/metabolism; Blood-Air Barrier/pathology; Bronchoalveolar Lavage Fluid/chemistry; Cells, Cultured; Humans; Hyaluronan Receptors/physiology*; Hyaluronic Acid/pharmacology*; Hydrochloric Acid/toxicity*; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase/physiology*; Pneumonia/chemically induced; Pneumonia/drug therapy*; Pneumonia/metabolism; Pneumonia/pathology; Pulmonary Gas Exchange; Viscosupplements/pharmacology