Abstract
Alveolar epithelial cells (AECs) are an essential part of the respiratory barrier in lungs for gas exchange and protection against pathogens. Damage to AECs occurs during lung injury and PAMPs/DAMPs have been shown to activate AECs. However, their interplay as well as the mechanism of AECs’ activation especially by the alarmin S100A8/A9 is unknown. Thus, our aim was to study the mechanism of activation of AECs (type I and type II) by S100A8 and/or lipopolysaccharide (LPS) and to understand the role of endogenous S100A8/A9 in neutrophil recruitment in the lung. For our studies, we modified a previous protocol for isolation and culturing of murine AECs. Next, we stimulated the cells with S100A8 and/or LPS and analyzed cytokine/chemokine release. We also analyzed the contribution of the known S100-receptors TLR4 and RAGE in AEC activation. In a murine model of lung injury, we investigated the role of S100A8/A9 in neutrophil recruitment to lungs. S100A8 activates type I and type II cells in a dose- and time-dependent manner which could be quantified by the release of IL-6, KC, and MCP-1. We here clearly demonstrate that AEC s are activated by S100A8 via a TLR4-dependent pathway. Surprisingly, RAGE, albeit mainly expressed in lung tissue, plays no role. Additionally, we show that S100A8/A9 is an essential factor for neutrophil recruitment to lungs. We, therefore, conclude that S100A8 promotes acute lung injury via Toll-like receptor 4-dependent activation of AECs.
Highlights
Acute lung injury (ALI) and especially the severe form acute respiratory distress syndrome (ARDS) is a life-threatening disease which encompasses severe lung inflammation leading to respiratory failure and is characterized by alveolar capillary barrier damage [1].Alveolar capillary barrier is formed of epithelium, interstitial space, and endothelium [2]
We focused on the role of the endogenous damage-associated molecular patterns (DAMPs) protein S100A8 in combination with the pathogen-associated molecular patterns (PAMPs) molecule lipopolysaccharide (LPS) in initiation of lung inflammation
Pathogen-associated molecular patterns like LPS trigger the release of DAMPs from activated alveolar macrophages in the alveoli
Summary
Acute lung injury (ALI) and especially the severe form acute respiratory distress syndrome (ARDS) is a life-threatening disease which encompasses severe lung inflammation leading to respiratory failure and is characterized by alveolar capillary barrier damage [1].Alveolar capillary barrier is formed of epithelium, interstitial space, and endothelium [2]. Acute lung injury (ALI) and especially the severe form acute respiratory distress syndrome (ARDS) is a life-threatening disease which encompasses severe lung inflammation leading to respiratory failure and is characterized by alveolar capillary barrier damage [1]. Alveolar epithelial type I cells (AECI) are large squamous cells which help in gas exchange [3, 4] and are renewed by differentiation of AECII to AECI [4]. Alveolar epithelial type II cells (AECII) are small cuboidal cells [3] which produce pulmonary. When AECI are damaged during ALI, gas exchange is hampered [5]. AECII injury causes decrease in surfactant production which leads to reduced lung compliance and impaired replacement of damaged AECI. AECII has been shown to differentiate into AECI during culture on fibronectin-coated plates for several days [6]
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