Chronic intermittent hypoxia decreases pulmonary clearance of 99mTc-labelled particulate matter in mice

Cuiping Fu; Huan Lu; Xu Wu; Jie Liu; Chengying Liu; Zilong Liu; Wei Yuan; Jian Zhou; Shanqun Li

Chronic intermittent hypoxia decreases pulmonary clearance of ^99mTc-labelled particulate matter in mice

Am J Transl Res. 2017 Jun 15;9(6):3060-3072. eCollection 2017.

Authors

Cuiping Fu¹, Huan Lu¹, Xu Wu¹, Jie Liu¹, Chengying Liu², Zilong Liu¹, Wei Yuan³, Jian Zhou¹, Shanqun Li¹

Affiliations

¹ Department of Pulmonary Medicine, Center of Snoring and Sleep Apnea Medicine, Zhongshan Hospital of Fudan UniversityShanghai 200032, China.
² Department of Respiratory Medicine, Affiliated Jiangyin Hospital of Southeast UniversityJiangyin 214400, China.
³ Department of Pathology Medicine, Zhongshan Hospital of Fudan UniversityShanghai 200032, China.

PMID: 28670393
PMCID: PMC5489905

Abstract

Background: Obstructive sleep apnea-hypopnea syndrome (OSAHS) could cause systematic inflammation including pulmonary inflammatory response, whereas the influence of OSAHS in pulmonary clearance ability remains unknown. The main pathophysiological feature of OSAHS is chronic intermittent hypoxia (CIH). The goal of this study is to clarify the airway clearance of particulate matter (PM) in CIH mice, and to explore the potential mechanism.

Methods: Balb/c mice were divided into a CIH group and a control group, exposed to intermittent hypoxia and air chamber, respectively. A radioactive probe, ^99mTc labeled PM, was endotracheally inserted into the mice at 10 mg/kg, with a starting dose of 800 μCi. The change of radioactive dose reserved in the lung was observed using single-photon emission computed tomography/computed tomography (SPECT/CT) and reconstructed data were analyzed. Special airway resistance (sRaw) of mice was measured by non-invasive airway mechanics sites. Lung resistive load (R_L), elastic resistance, and compliance were measured by a multichannel physiological signal system. Lung injury was judged by hematoxylin-eosin staining and histologic score. Change in mucus secretion was determined using periodic acid-Schiff staining and enzyme-linked immunosorbent assay. Fresh lung tissue was used for real-time polymerase chain reaction and western blot analysis to explore related change of inflammation and signaling molecules and potential mechanical pathway.

Results: Mice in the CIH group had higher PM radioactive deposit than the control group (93.37±3.44 μCi vs. 65.98±2.61 μCi). The average radiation dose in the lung was elevated (0.0005 μCi/mm³ vs. 0.0001383 μCi/mm³). Mice in the CIH group have higher value of sRaw, R_L, and elastic resistance, whereas pulmonary compliance decreased compared to the control group (2.13±0.29 mL/cmH₂O vs. 5.37±1.02 mL/cmH₂O). The CIH group showed a higher histopathological score. Several genes associated with mucin secretion such as chemokine (C-X-C motif) ligand 1 (CXCL1), Clara Cell Secretory Protein 16 (CC16), macrophage inflammatory protein 2 (MIP-2), chloride channel regulator 1 (Gob5), and mucin 5AC (MUC5AC) showed elevated expression. Phosphatidylinostol-3-kinase/serine/threonine-specific protein kinase (PI3K/AKT) pathway was activated in the CIH group.

Conclusions: CIH decreased pulmonary clearance of PM and increased lung airway resistance, which may be related to inflammatory response and mucus hypersecretion in the lung.

Keywords: Intermittent hypoxia; airway resistance; clearance; mucin; particulate matter.