Does activation of the FcgammaRIIa play a role in the pathogenesis of the acute lung injury/acute respiratory distress syndrome?

Abstract

ALI (acute lung injury) and its more severe form ARDS (acute respiratory distress syndrome) are inflammatory diseases of the lung characterized by hypoxaemia and diffuse bilateral infiltrates. Disruption of epithelial integrity and injury to endothelium are contributing factors of the development of ALI/ARDS, and alveolar damage is the most pronounced feature of ALI/ARDS. The resulting increase in lung microvascular permeability promotes influx of inflammatory cells to the alveolar spaces. Oedema fluid contains pro-nflammatory mediators and plasma proteins, including Igs (immunoglobulins). Moreover, several reports describe the presence of autoantibodies and immune complexes [anti-IL-8 (interleukin-8) autoantibody/IL-8 complexes] in lung fluids (oedema and bronchoalveolar lavage fluids) from patients with ALI/ARDS. These immune complexes associate with FcgammaRIIa (Fcgamma IIa receptor) in lungs of patients with ARDS. Furthermore, the expression of FcgammaRIIa is substantially elevated in lungs of these patients. FcgammaRIIa appears on virtually all myeloid cells, platelets and endothelial cells. It is a low-affinity receptor for IgG that preferentially binds aggregated immunoglobulins and immune complexes. FcgammaRs regulate phagocytosis and cell-mediated cytotoxicity, and initiate the release of inflammatory mediators. It should be noted that immune complexes formed between either anti-neutrophil autoantibodies and their specific antigens or anti-HLA (human leucocyte antigen) antibodies and target antigens are implicated in the pathogenesis of TRALI (transfusion-related acute lung injury), and importantly, animal studies indicate that FcgammaRs are essential for these complexes to cause damage to the lungs. Therefore, we hypothesize that FcgammaRs such as FcgammaRIIa could contribute to the pathogenesis of ALI/ARDS.

Figure 1. Events characterizing early stage of lung damage in patients with ALI/ARDS

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Figure 2. FcγRIIa signalling cascade

Activation of the Src kinases leads to the recruitment of a kinase from the Syk family followed by phosphorylation of a series of downstream proteins such as phosphoinositide 3-kinase (PI3-K). Subsequent events include production of PtdIns(3,4,5)P₃ and recruitment of Bruton's tyrosine kinase (BtK) and phospholipase Cγ (PLCγ). This leads to increased calcium mobilization and also triggers additional downstream signalling events as activation of the Ras/Raf/MAPK (mitogen-activated protein kinase) pathways [15,16]. DAG, diacylglycerol; ERK, extracellular-signal-regulated kinase; InsP₃, Ins(1,4,5)P₃; JNK, c-Jun N-terminal kinase; PKC, protein kinase C.

Figure 3. Expression of FcγRIIa and association of IL-8 in anti-IL-8 autoantibody/IL-8 immune complexes with FcγRIIa in normal lung tissues and tissues from ARDS patients

Left panels from the top: FcγRIIa (green)/IL-8 (red) x60. Big left panel: co-localization (yellow) of FcγRIIa (green) and IL-8 (red). Nuclei are stained blue. Right panels from the top: FcγRIIa (green)/IL-8 (red) ×60. Big right panel: co-localization (yellow) of FcγRIIa (green) and IL-8 (red). Nuclei are stained blue. Acquisition settings for the images were UV/567/647, and specific parameters for the fluorophores were Cy3 (red) excitation at 567 nm and emission at 600 nm, Alexa 647 (pseudo-colour green) excitation at 647 nm and emission at 700 nm. The sections were evaluated using a PerkinElmer Ultra VIEW LCI confocal imaging system with a Nikon TE2000-S fluorescence microscope and a PlanApo'60 immersion oil objective. Ultra VIEW Imaging Suite software (version 5.5.0.4) was used for image processing.