Susceptibility to Aspergillus Infections in Rats with Chronic Obstructive Pulmonary Disease via Deficiency Function of Alveolar Macrophages and Impaired Activation of TLR2.

Yuting Wu,Li Li,Deming Zhang,Hong Xu,Weifeng Yuan,Wenjie Huang

doi:10.1007/s10753-016-0363-x

Abstract

Clinical evidence indicates that patients with severe chronic obstructive pulmonary disease (COPD) are more susceptible to Aspergillus. However, the exact mechanisms underlying this effect are not known. In this study, we used cigarette smoke exposure to generate COPD rat model. colony-forming units (CFU) count assessment and phagocytosis were applied to evaluate the defense function of COPD rats against Aspergillus challenge. ELISA, western blotting, and GST-Rac1 pull-down assays were conducted to determine the expressions of cytokines and TLR2-associated signaling pathway. Our data showed that Aspergillus burdens increased, phagocytosis of Aspergillus as well as the expressions of inflammatory cytokines from alveolar macrophages (AMs) were impaired in COPD rats compared with normal rats. Though TLR2 signaling-related proteins were induced in response to the stimulation of Aspergillus or Pam3csk4 (TLR2 agonist), the activation of TLR2-associated signaling pathway was apparently interfered in rats with COPD, compared to that in normal rats. Taken together, our study demonstrated that COPD caused the deficiency of AMs function and impaired the activation of TLR2/PI3K/Rac 1 signaling pathway, leading to invasion of Aspergillus infection, which also provides a future basis for the infection control in COPD patients.

Highlights

Invasive pulmonary aspergillosis (IPA) is caused by Aspergillus and characterized as a life-threatening pneumonia due to lung parenchyma invasion with vasculature erosion and necrosis
Clinical evidence suggested that the incidence of invasive pulmonary aspergillosis (IPA) in the context of chronic obstructive pulmonary disease (COPD) is increasing, the mechanisms underlying this association are still poorly understood
We have demonstrated that CS-exposure substantially attenuated the clearance of Aspergillus

Summary

Introduction

Invasive pulmonary aspergillosis (IPA) is caused by Aspergillus and characterized as a life-threatening pneumonia due to lung parenchyma invasion with vasculature erosion and necrosis. Aspergillus species are widely distributed in nature and have no invasion to immunocompetent individuals owing to host immune defense system. Respiratory mucosal epithelial cells serve as an anatomic barrier to parenchymal invasion, promote mucociliary clearance, and ingest inhaled conidia [4]. Alveolar macrophages (AMs) consist of multiple kinds of immune cells within the alveolar space and act as a first line of innate host defense against inhaled conidia [5], which employ an array of receptors to recognize pathogenassociated molecular patterns (PAMPs) and to facilitate phagocytic uptake [6]

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Conclusion