Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PPL Therapeutics is developing transgenic alpha-1-antitrypsin for the treatment of cystic fibrosis lung disease and other conditions in which connective tissue is broken down irreversibly. AAT is a plasma protein that inhibits elastase, a key player in the inflammatory response that, unchecked, will lead to excessive tissue destruction. PPL has taken transgenic alpha-1-antitrypsin through phase II clinical trials in the cystic fibrosis lung, delivering it in aerosol form to assess its safety and efficacy [315887]. Although early results are not statistically relevant with respect to clinical benefit, they do show some promise, especially given the low numbers of patients studied and the complex phenotypes and severities associated with cystic fibrosis.
Curr Opin Mol Ther 2000 Apr
PMID:Technology evaluation: transgenic alpha-1-antitrypsin (AAT), PPL therapeutics. 1124 42

We previously demonstrated essential roles of the Fas-Fas ligand (FasL) pathway in bleomycin-induced pneumopathy in mice. T lymphocytes and natural killer cells express FasL on activation and use it as a cytotoxic effector molecule. Because interleukin (IL)-12 is known to play a critical role in cell-mediated immunity, we investigated whether anti-IL-12 antibody treatment suppresses the development of this model. The anti-IL-12 antibody treatment decreased the number of apoptotic cells and the degree of inflammation and fibrosis in lung tissue. The results of RT-PCR showed that IL-12p40, IL-12 receptor (R) beta2, interferon-gamma, tumor necrosis factor-alpha and FasL mRNAs were upregulated after bleomycin instillation. The upregulation of FasL, IL-12Rbeta2, and tumor necrosis factor-alpha mRNA expression in lung tissue was suppressed by anti-IL-12 antibody treatment. The results of enzyme-linked immunosorbent assay showed that the levels of IL-12p40, but not of IL-12p70, were increased in lung tissue after bleomycin instillation. Although the increase in IL-12Rbeta2 mRNA levels suggests that the T helper type 1 cell response may participate in lung injury, the increase in IL-12p40 supports T helper type 2 cell predominance in the fibrotic process of this model. The administration of anti-IL-12 antibody could be a novel therapy against lung injury and pulmonary fibrosis.
Am J Physiol Lung Cell Mol Physiol 2001 Jun
PMID:Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12. 1135 Jul 91

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling (ISEL) and propidium iodide staining; percent of alpha-smooth muscle actin (alpha-SMA) positive cells by fluorescence-activated cell sorter; and alpha1-(I) collagen, transforming growth factor (TGF)-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from IPF and control lungs. Growth rate was significantly lower in IPF fibroblasts compared with controls (13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d). Conversely, a significantly higher percentage of apoptotic cells was observed in IPF-derived fibroblasts (ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008). alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in IPF samples (62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01). IPF fibroblasts were characterized by an increase in pro-alpha1-(I) collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from IPF exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
Am J Respir Cell Mol Biol 2001 May
PMID:Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. 1135 Aug 29

A deficiency in alveolar surfactant due to immaturity of alveolar type II epithelial cells causes respiratory distress syndrome (RDS). In contrast to animals, the fetal maturation of surfactant in human lungs takes place before term, exceptionally large quantities of surfactant accumulating in the amniotic fluid. The antenatal development of surfactant secretion is very variable but corresponds closely to the risk of RDS. The variation in SP-A and SP-B genes, race, sex and perinatal complications influence susceptibility to RDS. Surfactant therapy has improved the prognosis of RDS remarkably. Abnormalities in alveolar or airway surfactant characterize many lung and airway diseases. In the acute respiratory distress syndrome, deficiencies in surfactant components (phospholipids, SP-B, SP-A) are evident, and may be caused by pro-inflammatory cytokines (IL-1, TNF) that decrease surfactant components. The resultant atelectasis localizes the disease, possibly allowing healing (regeneration, increase in surfactant). In the immature fetus, cytokines accelerate the differentiation of surfactant, preventing RDS. After birth, however, persistent inflammation is associated with low SP-A and chronic lung disease. A future challenge is to understand how to inhibit or redirect the inflammatory response from tissue destruction and poor growth towards normal lung development and regeneration.
Comp Biochem Physiol A Mol Integr Physiol 2001 May
PMID:Surfactant in respiratory distress syndrome and lung injury. 1136 52

Polymorphonuclear leukocyte-dominated airway inflammation is a major component of cystic fibrosis (CF) lung disease and may be associated with CF transmembrane conductance regulator (CFTR) dysfunction as well as infection. Mutant DeltaF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-kappaB. G551D mutants also lack Cl- channel function, but CFTR is trafficked normally. We compared the effects of CFTR mutations on the endogenous activation of an NF-kappaB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked DeltaF508 allele caused a sevenfold activation of NF-kappaB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-kappaB was also activated in 9/HTEo-/pCep-R cells and in 16HBE/pcftr antisense cell lines, which lack CFTR Cl- channel function but do not accumulate mutant protein in the ER. This endogenous activation of NF-kappaB was associated with elevated interleukin-8 expression. Impaired CFTR Cl- channel activity as well as cell stress due to accumulation of mistrafficked CFTR in the ER contributes to the endogenous activation of NF-kappaB in cells with the CFTR mutation.
Am J Physiol Lung Cell Mol Physiol 2001 Jul
PMID:Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function. 1140 47

Tumor necrosis factor-alpha receptor knockout (TNF-alphaRKO) mice have homozygous deletions of the genes that code for both the 55- and 75-kD receptors. The mice are protected from the fibrogenic effects of bleomycin, silica, and inhaled asbestos. The asbestos-exposed animals exhibit reduced expression of other peptide growth factors such as transforming growth factor (TGF)-alpha, platelet-derived growth factors, and TGF-beta. In normal animals, these and other cytokines are elaborated at high levels during the development of fibroproliferative lung disease, but there is little information available that has allowed investigators to establish the role of the individual growth factors in disease pathogenesis. Here, we show that overexpression of TGF-beta(1) by means of a replication-deficient adenovirus vector induces fibrogenesis in the lungs of the fibrogenic-resistant TNF-alphaRKO mice. The fibrogenic lesions developed in both the KO and background controls within 7 d, and both types of animals exhibited similar incorporation of bromodeoxyuridine. Interestingly, airway epithelial cell proliferation appeared to be suppressed, perhaps due to the presence of the TGF-beta(1), a well-known inhibitor of epithelial mitogenesis. Before these experiments, there was no information available that would provide a basis for predicting whether or not TGF-beta(1) expression induces fibroproliferative lung disease in fibrogenic-resistant TNF-alphaRKO mice, an increasingly popular animal model.
Am J Respir Cell Mol Biol 2001 Jul
PMID:Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease. 1147 67

Gene replacement therapy represents an interesting new approach for the treatment of cystic fibrosis (CF) lung disease. Basic research suggests that CF gene therapy is feasible, but major technological challenges must be addressed before clinical applications are likely to succeed. Therapeutic genes can be delivered to and expressed in human airways, but the number of cells expressing the transgene is relatively low. The inefficiency of gene delivery is largely attributable to the remarkable defenses of human airways. Maintaining long-term transgene expression in airway cells is also a significant obstacle. Recent advances have been made in the development of vectors, expression cassettes, and delivery techniques for enhancing airway gene transfer and expression. These advances have the potential to improve the efficiency of lung gene therapy and to achieve clinical benefits for CF patients in the future.
Mol Ther 2001 Aug
PMID:Challenges and strategies for cystic fibrosis lung gene therapy. 1148 78

Although the lung is protected by classic innate and adaptive immune mechanisms, another unique local immunoregulatory system involving pulmonary surfactant is described in this review. Normal surfactant inhibits many immune cell functions including proliferation resulting from various stimuli and production of reactive oxidants, inflammatory mediators, and some cell surface markers. The predominant surfactant lipids appear to be responsible for these suppressive effects. Conversely, surfactant proteins SP-A and SP-D stimulate many aspects of immune cell behavior. These proteins are collagenous lectins or collectins that bind to glycoconjugates on many pathogens, enhancing phagocytosis and killing in some cases. SP-A and SP-D stimulate chemotaxis and reactive oxidant generation, particularly in macrophages, although other cells are probably affected as well. In some cases, SP-A also stimulates the expression of cell surface markers and is involved in the stimulation of inflammatory mediators. Under normal conditions, the inhibitory effects of the lipid prevail, but the collectins may provide focal activation and stimulate immune cells at sites where they are needed. However, in some types of lung disease or after certain insults or exposures, the balance between these inhibitory and stimulatory influences may be disrupted and result in inflammatory injury.
Pediatr Pathol Mol Med
PMID:Surfactant regulation of host defense function in the lung: a question of balance. 1148 34

The bronchiolar-alveolar epithelium (BAE) is a primary target site for inhaled agents that cause lung injury. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis (IPF). A number of peptide growth factors (GF) have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse BAE and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms (PDGF) A and B, transforming growth factor beta-1 (TGF-beta(1)), and tumor necrosis factor alpha (TNF-alpha). A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the BAE cells to greater than 85% (80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells) in culture. Northern analysis, RNase protection assay, and immunocytochemistry (ICC) were used to establish mRNA and protein expression of the GF over time in the cultured BAE and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with TNF-alpha upregulates expression of TGF-beta(1). The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. TGF-beta(1) is expressed constitutively by BAE and mesenchymal cells, whereas TNF-alpha expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
Exp Mol Pathol 2001 Aug
PMID:TNF-alpha, PDGF, and TGF-beta(1) expression by primary mouse bronchiolar-alveolar epithelial and mesenchymal cells: tnf-alpha induces TGF-beta(1). 1150 94

The pulmonary neuroendocrine cell system comprises solitary neuroendocrine cells and clusters of innervated cells or neuroepithelial bodies (NEBs). NEBs figure prominently during the perinatal period when they are postulated to be involved in physiological adaptation to air breathing. Previous studies have documented hyperplasia of NEBs in cystic fibrosis (CF) lungs and increased neuropeptide (bombesin) content produced by these cells, possibly secondary to chronic hypoxia related to CF lung disease. However, little is known about the role of NEBs in the pathogenesis of CF lung disease. In the present study, using a panel of cystic fibrosis transmembrane conductance regulator (CFTR)-specific antibodies and confocal microscopy in combination with RT-PCR, we demonstrate expression of CFTR message and protein in NEB cells of rabbit neonatal lungs. NEB cells expressed CFTR along with neuroendocrine markers. Confocal microscopy established apical membrane localization of the CFTR protein in NEB cells. Cl(-) conductances corresponding to functional CFTR were demonstrated in NEB cells in a fresh lung slice preparation. Our findings suggest that NEBs, and related neuroendocrine mechanisms, likely play a role in the pathogenesis of CF lung disease, including the early stages before establishment of chronic infection and chronic lung disease.
Am J Physiol Lung Cell Mol Physiol 2001 Sep
PMID:Expression of CFTR and Cl(-) conductances in cells of pulmonary neuroepithelial bodies. 1150


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