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1.
Am J Respir Cell Mol Biol ; 41(2): 155-69, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19109244

ABSTRACT

Our previous studies revealed that the presence in lung fluids of anti-IL-8 autoantibody:IL-8 immune complexes is an important prognostic indicator for the development and outcome of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Anti-IL-8:IL-8 complexes purified from lung edema fluids trigger chemotaxis of neutrophils, induce activation of these cells, and regulate their apoptosis, all via IgG receptor, FcgammaRIIa. Importantly, increased levels of FcgammaRIIa are present in lungs of patients with ARDS, where FcgammaRIIa is partially associated with anti-IL-8:IL-8 complexes. In the current study, we demonstrate the ability of anti-IL-8:IL-8 complexes to promote an inflammatory phenotype of human umbilical vein endothelial cells via interaction with FcgammaRIIa. Human umbilical vein endothelial cells cultured in the presence of the complexes become activated, as shown by increased phosphorylation of ERK, JNK, and Akt, and augmented nuclear translocation of NF-kappaB. Anti-IL-8:IL-8 complexes also up-regulate expression of intracellular adhesion molecule (ICAM)-1 on the cell surface. Furthermore, we detected increased levels of ICAM-1 on lung endothelial cells from mice in which lung injury was induced by generating immune complexes in alveolar spaces. On the other hand, ICAM-1 expression was unchanged in lungs of gamma chain-deficient mice, lacking receptors that interact with immune complexes. Moreover, in lung tissues from patients with ARDS, anti-IL-8:IL-8 complexes were associated with endothelial cells that expressed higher levels of ICAM-1. Our current findings implicate that anti-chemokine autoantibody:chemokine immune complexes, such as IL-8:IL-8 complexes, may contribute to pathogenesis of lung inflammation by inducing activation of endothelial cells through engagement of IgG receptors.


Subject(s)
Antigen-Antibody Complex/immunology , Autoantibodies/immunology , Endothelial Cells/immunology , Interleukin-8/immunology , Receptors, IgG/immunology , Animals , Antigens, CD34/metabolism , Cells, Cultured , Endothelial Cells/cytology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Intercellular Adhesion Molecule-1/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Proto-Oncogene Proteins c-akt/metabolism , Receptors, IgG/genetics , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Signal Transduction/physiology , Transcription Factor RelA/metabolism
2.
Am J Respir Cell Mol Biol ; 37(5): 532-43, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17585113

ABSTRACT

We have shown previously that high concentrations of IL-8 associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes) are present in lung fluids from patients with the acute respiratory distress syndrome (ARDS), and correlate both with the development and outcome of ARDS. We also detected deposition of these complexes in lung tissues from patients with ARDS but not in control tissues. Moreover, we determined that IgG receptors (FcgammaRs) mediate activity of anti-IL-8:IL-8 complexes. In the current study, we generated anti-KC (KC = chemokine (CXC motif) ligand 1 (CXCL1)) autoantibody:KC immune complexes (KC-functional IL-8) in lungs of mice to develop a mouse model of autoimmune complex-induced lung inflammation. Both wild-type (WT) and gamma-chain-deficient mice that lack receptors for immune complexes (FcgammaRs) were studied. First, the mice were immunized with KC to induce anti-KC autoantibodies. Then, KC was administered intratracheally to generate anti-KC:KC complexes in the lung. Presence of anti-KC:KC complexes was associated with development of severe pulmonary inflammation that was, however, dramatically suppressed in gamma-chain-deficient mice. Second, because sepsis is considered the major risk factor for development of ARDS, we evaluated LPS-treated WT as well as gamma-chain-deficient mice for the presence of anti-KC:KC complexes and pulmonary inflammatory responses. We detected complexes between anti-KC autoantibodies and KC in lung lavages and tissues of mice treated with LPS. Moreover, gamma-chain-deficient mice that lack receptors for immune complexes were protected from LPS-induced pulmonary inflammation. Our results suggest that immune complexes containing autoantibodies contribute to development of lung inflammation in LPS-treated mice.


Subject(s)
Antigen-Antibody Complex/adverse effects , Autoantibodies/adverse effects , Chemokine CXCL1/immunology , Lung/immunology , Lung/pathology , Pneumonia/immunology , Pneumonia/pathology , Receptors, IgG/physiology , Animals , Disease Models, Animal , Immune Complex Diseases/immunology , Immune Complex Diseases/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Severity of Illness Index
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