ABSTRACT
Oxidant-induced injury to the lung causes extensive damage to lung epithelial cells. Impaired protection and repair of the lung epithelium can result in death. The serine-threonine kinase Akt has been implicated in inhibiting cell death induced by different stimuli including growth factor withdrawal, cell cycle discordance, DNA damage, and loss of cell adhesion in different cell types. However, the in vivo relevance of this prosurvival pathway has not been explored. Here we show that a constitutively active form of Akt introduced intratracheally into the lungs of mice by adenovirus gene transfer techniques protects mice from hyperoxic pulmonary damage and delays death of mice. This is the first demonstration of the in vivo protective function of Akt in the context of oxidant-induced lung injury.
Subject(s)
Hyperoxia/mortality , Lung/drug effects , Oxidants/adverse effects , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Carrier Proteins/metabolism , Epithelial Cells/metabolism , Forkhead Transcription Factors , Humans , Mice , Nuclear Proteins/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt , Transcription Factors/metabolism , bcl-Associated Death ProteinABSTRACT
The chemokine regulated on activation normal T cells expressed and secreted (RANTES) has been implicated in eosinophil chemotaxis in asthma and allergic diseases, which are thought to be T helper (Th) type 2-dominated diseases. However, adoptive transfer of Th1 cells in mice upregulates RANTES gene expression in the lung, and increased RANTES expression has been documented in several Th1 cell-dominated conditions that are associated with neutrophilia. The in vivo role of RANTES in the pathogenesis of disease processes is not well understood. To determine the effect of RANTES expression alone in vivo, we generated transgenic mice that overexpress RANTES specifically in the lung in an inducible fashion. The airways of the transgenic mice overexpressing RANTES displayed a significant increase in neutrophil infiltration compared with that in control mice. The increased airway neutrophilia was also evident when the transgenic mice were tested in a murine model of allergic airway inflammation. RANTES expression also induced expression of the chemokine genes macrophage inflammatory protein-2, 10-kDa interferon-gamma-inducible protein, and monocyte chemoattractant protein-1 in the lungs of the transgenic mice. Our studies highlight a hitherto unappreciated role for RANTES in neutrophil trafficking during inflammation. Thus increased RANTES expression, as observed during respiratory viral infections, may play an important role in the associated neutrophilia and exacerbations of asthma.
Subject(s)
Chemokine CCL5/genetics , Gene Expression Regulation/physiology , Lung/physiology , Neutrophils/physiology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Cell Line , Chemokine CCL5/physiology , Crosses, Genetic , Doxorubicin/pharmacology , Eosinophils/physiology , Gene Expression Regulation/drug effects , Human Growth Hormone/genetics , Humans , Lung/cytology , Lung/drug effects , Lymphocyte Activation , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organ Specificity , Promoter Regions, Genetic , Recombinant Proteins/biosynthesis , T-Lymphocytes/immunology , T-Lymphocytes/physiologyABSTRACT
The cytokines IL-4, IL-5, and IL-13, secreted by Th2 cells, have distinct functions in the pathogenesis of asthma. We have previously shown that the transcription factor GATA-3 is expressed in Th2 but not Th1 cells. However, it was unclear whether GATA-3 controls the expression of all Th2 cytokines. Expression of a dominant-negative mutant of GATA-3 in mice in a T cell-specific fashion led to a reduction in the levels of all the Th2 cytokines IL-4, IL-5, and IL-13. Airway eosinophilia, mucus production, and IgE synthesis, all key features of asthma, were severely attenuated in the transgenic mice. Thus, targeting GATA-3 activity alone is sufficient to blunt Th2 responses in vivo, thereby establishing GATA-3 as a potential therapeutic target in the treatment of asthma and allergic diseases.
