transforming-growth-factor-alpha and Pneumonia

The production of pulmonary surfactant, a complex of lipids and proteins that reduces surface tension at the alveolar air-liquid interface, is developmentally regulated. Several hormones, most notably glucocorticoids, are known to accelerate maturation of the surfactant system. Cytokines are polypeptides that act mostly in a paracrine fashion and possess a wide spectrum of activities on multiple types of cells. Many cytokines are produced by different lung cells a various stages of fetal development or under pathological conditions affecting the fetus. In addition, cytokines present in amniotic fluid or in the blood stream may reach the fetal lungs. Some cytokines, including epidermal growth factor, transforming growth factor-alpha, and interferon-gamma have been shown to stimulate the production of surfactant components. On the other hand, tumor necrosis factor and transforming growth factor-beta downregulate the production of surfactant lipids and proteins. We have recently shown that the proinflammatory cytokine interleukin-1 (IL-I) enhances the expression of surfactant protein A (SP-A) in fetal rabbit lung explants. In addition, injection of IL-I into the amniotic fluid of fetal rabbits enhances the expression of surfactant proteins and improves the lung compliance of preterm animals. Preterm delivery is often associated with subclinical intraamniotic infection. In these cases, amniotic fluid concentrations of IL-I are often elevated. We propose that this cytokine accelerates maturation of the surfactant system in fetal lungs and thus prepares the fetus for extrauterine life.

Topics: Animals; Cell Differentiation; Cytokines; Embryonic and Fetal Development; Epidermal Growth Factor; Humans; Pneumonia; Pulmonary Surfactants; Transforming Growth Factor alpha; Transforming Growth Factor beta

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.

Topics: ADAM17 Protein; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line; Epithelial Cells; ErbB Receptors; Gefitinib; Heparin-binding EGF-like Growth Factor; Humans; Lung; Lung Injury; Lung Neoplasms; Mice; Mice, Transgenic; Models, Animal; p38 Mitogen-Activated Protein Kinases; Pneumonia; Protein Kinase Inhibitors; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha

In acute pulmonary inflammation, danger is first recognized by epithelial cells lining the alveolar lumen and relayed to vascular responses, including leukocyte recruitment and increased endothelial permeability. We supposed that this inflammatory relay critically depends on the immunological function of lung interstitial cells such as smooth muscle cells (SMC). Mice with smooth muscle protein-22α promotor-driven deficiency of the disintegrin and metalloproteinase (ADAM) 17 (SM22-Adam17(-/-)) were investigated in models of acute pulmonary inflammation (LPS, cytokine, and acid instillation). Underlying signaling mechanisms were identified in cultured tracheal SMC and verified by in vivo reconstitution experiments. SM22-Adam17(-/-) mice showed considerably decreased cytokine production and vascular responses in LPS- or acid-induced pulmonary inflammation. In vitro, ADAM17 deficiency abrogated cytokine release of primary SMC stimulated with LPS or supernatant of acid-exposed epithelial cells. This was explained by a loss of ADAM17-mediated growth factor shedding. LPS responses required ErbB1/epidermal growth factor receptor transactivation by TGFα, whereas acid responses required ErbB4 transactivation by neuregulins. Finally, LPS-induced pulmonary inflammation in SM22-Adam17(-/-) mice was restored by exogenous TGFα application, confirming the involvement of transactivation pathways in vivo. This highlights a new decisive immunological role of lung interstitial cells such as SMC in promoting acute pulmonary inflammation by ADAM17-dependent transactivation.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Cells, Cultured; Epithelial Cells; ErbB Receptors; Humans; Leukocytes; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Microfilament Proteins; Muscle Proteins; Myocytes, Smooth Muscle; Oncogene Proteins v-erbB; Pneumonia; Promoter Regions, Genetic; Receptor, ErbB-4; Transcriptional Activation; Transforming Growth Factor alpha

To determine whether overexpression of transforming growth factor (TGF)-alpha in the adult lung causes remodeling independently of developmental influences, we generated conditional transgenic mice expressing TGF-alpha in the epithelium under control of the doxycycline (Dox)-regulatable Clara cell secretory protein promoter. Two transgenic lines were generated, and following 4 days of Dox-induction TGF-alpha levels in whole lung homogenate were increased 13- to 18-fold above nontransgenic levels. After TGF-alpha induction, transgenic mice developed progressive pulmonary fibrosis and body weight loss, with mice losing 15% of their weight after 6 wk of TGF-alpha induction. Fibrosis was detected within 4 days of TGF-alpha induction and developed initially in the perivascular, peribronchial, and pleural regions but later extended into the interstitium. Fibrotic regions were composed of increased collagen and cellular proliferation and were adjacent to airway and alveolar epithelial sites of TGF-alpha expression. Fibrosis progressed in the absence of inflammatory cell infiltrates as determined by histology, without changes in bronchiolar alveolar lavage total or differential cell counts and without changes in proinflammatory cytokines TNF-alpha or IL-6. Active TGF-beta in whole lung homogenate was not altered 1 and 4 days after TGF-alpha induction, and immunostaining was not increased in the peribronchial/perivascular areas at all time points. Chronic epithelial expression of TGF-alpha in adult mice caused progressive pulmonary fibrosis associated with increased collagen and extracellular matrix deposition and increased cellular proliferation. Induction of pulmonary fibrosis by TGF-alpha was independent of inflammation or early activation of TGF-beta.

Topics: Age Factors; Animals; Anti-Bacterial Agents; Cell Division; Collagen; Disease Progression; Doxycycline; Extracellular Matrix Proteins; Gene Expression; Mice; Mice, Transgenic; Pneumonia; Pulmonary Fibrosis; Transforming Growth Factor alpha; Transforming Growth Factor beta

To determine the role of transforming growth factor-alpha (TGF-alpha) in protecting the lung from aerosolized nickel injury, transgenic mouse lines expressing human TGF-alpha in the pulmonary epithelium, under control of the human surfactant protein-C gene promoter, were tested. Higher expressing TGF-alpha transgenic mouse lines, expressing distinct levels of TGF-alpha, survived longer than nontransgenic control mice. Increased survival correlated with levels of TGF-alpha expression in the lung. After 72 h of nickel exposure (70 microg Ni/m3), transgenic lines with intermediate levels of the TGF-alpha expression demonstrated attenuation of lung injury. The highest expressing line (line 28) demonstrated reduced lung inflammation and edema, reduced lung wet-to-dry weight ratios, decreased bronchoalveolar lavage (BAL) protein and neutrophils, reduced interleukin (IL)-1beta, interleukin-6, and macrophage inflammatory protein-2, and maintained surfactant protein-B (SP-B) levels compared with nontransgenic controls. In the TGF-alpha transgenic mouse model, TGF-alpha protects against nickel-induced acute lung injury, at least in part, by attenuating the inflammatory response, reducing pulmonary edema, and preserving levels of SP-B.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Dose-Response Relationship, Drug; Humans; Lung; Mice; Mice, Transgenic; Neoplasm Proteins; Neutrophils; Nickel; Organ Size; Pneumonia; Poly(ADP-ribose) Polymerases; Proteins; Proteolipids; Pulmonary Edema; Pulmonary Surfactants; Survival Rate; Transforming Growth Factor alpha

Topics: Anorexia; Bottle Feeding; Breast Feeding; Docosahexaenoic Acids; Energy Intake; Erythrocyte Membrane; Humans; Infant; Infant, Newborn; Interleukin-1; Pneumonia; Transforming Growth Factor alpha

To determine whether idiopathic pneumonia syndrome (IPS), a form of noninfectious lung injury that follows bone marrow transplantation, is associated with cytokine activation and increased susceptibility to lipopolysaccharide (LPS).. Case series.. Tertiary referral center for marrow transplantation.. Recipients with biopsy-confirmed IPS; normal volunteers and marrow transplant recipients without IPS were analyzed as controls.. Levels of lymphocyte and macrophage-derived cytokines as well as components of the LPS, LPS-binding protein (LBP), and CD14 system in bronchoalveolar lavage (BAL) fluid were determined. We found evidence of increased vascular permeability (BAL protein) and inflammatory cytokine activation (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor-alpha) in patients with IPS. Patients without IPS had BAL fluid cytokine and protein levels that were similar to levels in BAL fluid from normal volunteers. Moreover, components of the LPS amplification system (LBP and soluble CD14) were increased in patients with IPS but not in patients without IPS.. These results provide direct evidence for proinflammatory cytokine activation in IPS and suggest that these patients might be at increased risk for LPS-mediated injury through the LBP amplification pathway.

Topics: Acute-Phase Proteins; Adolescent; Adult; Bone Marrow Transplantation; Bronchi; Bronchoalveolar Lavage Fluid; Carrier Proteins; Case-Control Studies; Cytokines; Humans; Interleukin-1; Interleukin-2; Interleukin-6; Lipopolysaccharide Receptors; Lipopolysaccharides; Membrane Glycoproteins; Middle Aged; Pneumonia; Pulmonary Alveoli; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha

Although transforming growth factor-alpha (TGF-alpha) is widely distributed in transformed cells and in some normal cells and much is known about its structure and metabolism, there is little information about its physiological actions. TGF-alpha is not thought to be synthesized by nontransformed fibroblasts, but it is thought to be a mitogen for these and epithelial cells (Derynck, R. (1986) J. Cell. Biochem. 32, 293-304). We report here that fibroblasts obtained from hamsters with oxidant-induced lung injury release TGF-alpha at levels comparable with those reported for transformed cells. In conditioned media, one isoform of 18 kDa was recognized by a monoclonal antibody to mature TGF-alpha; five isoforms ranging from 18 to 42 kDa were recognized in cell lysates. Conditioned media from these fibroblasts stimulated tyrosine phosphorylation of the epidermal growth factor (EGF)/TGF-alpha receptor, competed with radioactive EGF for binding sites on A431 cells, and were mitogenic for mesenchymal and epithelial cells. This mitogenic activity could be almost completely blocked by anti-TGF-alpha. Conditioned media from normal lung fibroblasts exhibited none of these activities. Using normal lung fibroblasts, we found that TGF-alpha synthesis could be induced in vitro with 25 nmol/ml EGF, suggesting that the induction in vivo may have been due, in part, to a stimulation by EGF (or TGF-alpha) released by other cell types such as alveolar macrophages recruited to the injury site. TGF-alpha is, in general, a mitogen for epithelial cells (Derynck, 1986); more specific to acute injury in the lung, it may affect the proliferation (Ryan, R. M., Mineo-Kuhn, M. M., Kromer, C. M., and Finkelstein, J. N. (1994) Am. J. Physiol. 266, L17-L23) and metabolic activities (Whitsett, J. A., Weaver, T. E., Lieberman, M. A., Clark, J. G., and Daugherty, C. (1987) J. Biol. Chem. 262, 7908-7913) of alveolar epithelial type II cells. This is, we believe, the first report of a fibroblast-derived TGF-alpha induced with oxidant injury. If this response was ubiquitously manifested in other tissues, then fibroblast-derived TGF-alpha might be an important determinant of the epithelial and mesenchymal hyperplasia commonly observed in tissue repair.

Topics: Acute Disease; Animals; Base Sequence; Cells, Cultured; Cricetinae; Epidermal Growth Factor; Fibroblasts; Lung; Molecular Sequence Data; Oxidative Stress; Pneumonia; RNA, Messenger; Transforming Growth Factor alpha