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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that a failure of pulmonary endothelial cell survival induced by vascular endothelial growth factor (VEGF) receptor blockade results in lung alveolar septal cell apoptosis and emphysema. Because apoptosis and oxidative stress may be pathobiologically linked, we hypothesized that oxidative stress has a central role in alveolar septal cell apoptosis and emphysema induced by VEGF receptor blockade. When compared with control animals, rats treated with the VEGF receptor blocker SU5416 showed increased alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress, all of which were prevented by the superoxide dismutase mimetic M40419. The preservation of lung structure in SU5416+M40419-treated lungs was associated with increased septal cell proliferation, and enhanced phosphorylation of the prosurvival and antiapoptotic Akt, when compared with SU5416-treated lungs. Consistent with a positive feedback interaction between oxidative stress and apoptosis, we found that apoptosis predominated in areas of oxidative stress, and that apoptosis blockade by a broad spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. Oxidative stress and apoptosis, which cause lung cellular destruction in emphysema induced by VEGF receptor blockade, may be important mediators common to human and experimental emphysema.
Am J Respir Cell Mol Biol 2003 Jul
PMID:Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. 1260 Aug 22

Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell proliferation leading to tissue destruction and cyst formation. We demonstrate that serum response factor (SRF), a critical smooth muscle transcription factor, is overexpressed in LAM cells. To determine whether abnormal SRF levels might have a pathogenic role in LAM, we transfected SRF into mouse lung fibroblasts and performed a cDNA array analysis. High SRF level upregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-14, two MMPs previously shown to be increased in LAM. In addition, SRF down-regulated tissue inhibitor of metalloproteinase (TIMP)-3, one of their inhibitors. TIMP-3 inhibition was further confirmed by reverse transcriptase/polymerase chain reaction, immunoblotting, and immunostaining of human lung fibroblasts transfected with SRF fused to DsRed2 (a red variant of green fluorescent protein). To determine the in vivo significance of our findings, we immunostained 12 LAM cases for TIMP-3. In eight of them, TIMP-3 was ubiquitously present in normal lung parenchyma, but it was absent in LAM lesions. In the remaining cases, including two out of five normal control lungs, the antibody immunoreacted exclusively with elastin, probably due to suboptimal tissue processing. Because timp-3-null mice develop spontaneous emphysema, our findings suggest that SRF-mediated TIMP-3 inhibition might contribute to the tissue damage seen in LAM.
Am J Respir Cell Mol Biol 2003 Apr
PMID:Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression. 1270 9

Mice with lung-specific expression of human matrix metalloproteinase-1 (MMP-1) develop emphysematous changes similar to those seen in smoking-induced emphysema in humans. Morphometric analyses of three transgenic lines [homozygous colony (Col) 34, Col 50, and Col 64] with varying temporal expression of MMP-1 were undertaken to determine the validity of this animal as a model of adult-onset emphysema. Line 50 mice, which have early expression of MMP-1 (14 days postconception), exhibited morphometric changes by 5 days of age. In contrast, homozygous line 34 and 64 with delayed expression (birth and 2 wk of age) were normal up until 4 wk of age when progressive changes in their mean linear intercept were first noted. In contrast, heterozygous mice from line 34 with lower transgene expression did not develop emphysema until 1 yr of age. The changes in mean linear intercept coincided with an increase in lung compliance. Emphysema in these mice was associated with decreased immunostaining for type III collagen within the alveolar septa. This study provides evidence that MMP-1 induces progressive adult-onset emphysema by the selective degradation of type III collagen within the alveolar wall.
Am J Physiol Lung Cell Mol Physiol 2003 May
PMID:Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung. 1267 63

Pulmonary emphysema is characterized by alveolar wall destruction and airspace enlargement. Recent evidence indicates that epithelial or endothelial apoptosis may be involved in the pathogenesis of emphysema. Here, we describe the induction of emphysematous changes, including airspace enlargement, alveolar wall destruction, and enhanced lung distensibility, in mice receiving a single intratracheal injection of active caspase-3 and Chariot, a newly developed protein transfection reagent. Epithelial apoptosis and enhanced elastolytic activity (optimal at pH 5.5) in bronchoalveolar lavage were noted. Emphysematous changes were also generated in mice receiving an intratracheal injection of nodularin, a proapoptotic serine/threonine kinase inhibitor. This murine model provides direct evidence that confirms that alveolar wall apoptosis causes emphysematous changes. Furthermore, this simple technique for protein transfection of lung tissue can be used in a variety of future applications.
Am J Respir Cell Mol Biol 2003 May
PMID:Alveolar wall apoptosis causes lung destruction and emphysematous changes. 1270 10

Emphysema is characterized by enlargement of the distal airspaces in the lungs due to destruction of alveolar walls. Alveolar endothelial and epithelial cell apoptosis induced by cigarette smoke is thought to be a possible mechanism for this cell loss. In contrast, our studies show that cigarette smoke condensate (CSC) induces necrosis in alveolar epithelial cells and human umbilical vein endothelial cells. Furthermore, study of the cell death pathway in a model system using Jurkat cells revealed that in addition to inducing necrosis, CSC inhibited apoptosis induced by staurosporine or Fas ligation, with both effects prevented by the antioxidants glutathione and dithiothreitol. Time course experiments revealed that CSC inhibited an early step in the caspase cascade, whereby caspase-3 was not activated. Moreover, cell-free reconstitution of the apoptosome in cytoplasmic extracts from CSC-treated cells, by addition of cytochrome-c and dATP, did not result in activation of caspases-3 or -9. Thus, smoke treatment may alter the levels of pro- and antiapoptogenic factors downstream of the mitochondria to inhibit active apoptosome formation. Therefore, unlike previous studies, cell death in response to cigarette smoke by necrosis and not apoptosis may be responsible for the loss of alveolar walls and inflammation observed in emphysema.
Am J Respir Cell Mol Biol 2003 Nov
PMID:Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. 1274 58

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous inherited disease causing hypopigmentation and prolonged bleeding times. An additional serious clinical problem of HPS is the development of lung pathology, which may lead to severe lung disease and premature death. No cure for the disease exists, and previously, no animal model for the HPS lung abnormalities has been reported. A mouse model of HPS, which is homozygously recessive for both the Hps1 (pale ear) and Hps2 (pearl) genes, exhibits striking abnormalities of lung type II cells. Type II cells and lamellar bodies of this mutant are greatly enlarged, and the lamellar bodies are engorged with surfactant. Mutant lungs accumulate excessive autofluorescent pigment. The air spaces of mutant lungs contain age-related elevations of inflammatory cells and foamy macrophages. In vivo measurement of lung hysteresivity demonstrated aberrant lung function in mutant mice. All these features are similar to the lung pathology described in HPS patients. Morphometry of mutant lungs indicates a significant emphysema. These mutant mice provide a model to further investigate the lung pathology and therapy of HPS. We hypothesize that abnormal type II cell lamellar body structure/function may predict future lung pathology in HPS.
Am J Physiol Lung Cell Mol Physiol 2003 Sep
PMID:Aberrant lung structure, composition, and function in a murine model of Hermansky-Pudlak syndrome. 1277 51

Matrix metalloproteinase (MMP)-9 from alveolar macrophages is a major source of elastolytic activity in the lung. It is increased in the bronchoalveolar lavage fluid of patients with emphysema. Although the importance of macrophage-derived elastolytic activity in the pathogenesis of emphysema is well established, questions remain about MMP-9 regulation and activity. Because surfactant protein A (SP-A) is capable of modulating other functions of human monocytic cells, we hypothesized that SP-A may regulate MMP-9 expression. Vitamin D3-differentiated THP-1 cells and peripheral blood mononuclear cells were stimulated in vitro with several concentrations of SP-A for different incubation times. MMP-9 mRNA expression was measured by dot-blot analysis, gelatinolytic activity in the medium was determined by gel zymography, protein expression was determined by ELISA, and a specific MMP-9 activity assay was used to measure the state of activation of this enzyme in the cell supernatants. SP-A induced the expression of MMP-9 in both cell types, the effect was time and dose dependent, and MMP-9 was released in its zymogen form. On the basis of results of neutralizing antibody studies, we believe that SP-A action is mediated through Toll-like receptor-2. Even though the biological meaning of these findings remains to be elucidated, these observations suggest the presence of a novel, locally controlled mechanism by which MMP-9 levels may be regulated in alveolar macrophages. We speculate that SP-A may influence the protease/antiprotease balance in the lungs of patients with quantitative and/or qualitative changes in surfactant constituents favoring an abnormal breakdown of extracellular matrix components.
Am J Physiol Lung Cell Mol Physiol 2003 Oct
PMID:Surfactant protein A increases matrix metalloproteinase-9 production by THP-1 cells. 1284 7

Surfactant protein (SP)-D, a 43-kD multifunctional collagen-like lectin, is synthesized and secreted by the airway epithelium. SP-D knockout (SP-D [-/-]) mice exhibit an increase in the number and size of airway macrophages, peribronchiolar inflammation, increases in metalloproteinase activity, and development of emphysema. Nitric oxide (NO) is involved in a variety of signaling processes, and because altered NO metabolism has been observed in inflammation, we hypothesized that alterations in its metabolism would underlie the proinflammatory state observed in SP-D deficiency. Examination of the bronchial alveolar lavage (BAL) from SP-D (-/-) mice reveals a significant increase in protein and phospholipid content and total cell count. NO production and inducible NO synthase expression were increased in the BAL; however, there was a decline in S-nitrosothiol (SNO) content in the BAL and a loss of SNO immunoreactivity within the tissue. This decline in SNO was accompanied by an increase in nitrotyrosine staining. We conclude that inflammation that occurs in SP-D deficiency results in an increase in NO production and a shift in the chemistry and targets of NO. We speculate that the proinflammatory response due to SP-D deficiency results, in part, from a disruption of NO-mediated signaling within the innate immune system.
Am J Respir Cell Mol Biol 2004 Mar
PMID:Surfactant protein-D, a mediator of innate lung immunity, alters the products of nitric oxide metabolism. 1287 50

Elastase degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. In addition to elastolytic activities, elastases release growth factors from extracellular matrices and interstitial cell surfaces that can regulate elastogenesis and other cellular responses. In the present study, we demonstrate that brief treatment of matrix-laden rat pulmonary fibroblast cultures with pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) concomitant with a decrease in HB-EGF binding to both heparan sulfate proteoglycan and receptor sites on the cells. In undigested, matrix-laden fibroblasts, HB-EGF significantly downregulates elastin mRNA via activation of epidermal growth factor receptor. Results from nuclear run-on analyses show that HB-EGF downregulates elastin mRNA via transcriptional suppression. HBEGF treatment stimulates MAP or ERK kinase (MEK)-dependent ERK1/2 phosphorylation and leads to nuclear accumulation of Fra-1. Blocking ERK1/2 activation by MEK1/2 inhibitors (PD-98059 or U-0126) diminishes HB-EGF-induced Fra-1 accumulation and subsequent downregulation of elastin mRNA. Coaddition of two elastase-released growth factors, HB-EGF and FGF-2, results in an additive inhibitory effect on elastin mRNA levels. Furthermore, HB-EGF addition to pulmonary fibroblasts increases FGF-2 mRNA and protein levels. These data suggest that HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/repair situations.
Am J Physiol Lung Cell Mol Physiol 2003 Nov
PMID:Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts. 1288 62

Both first-hand and second-hand [i.e. side-stream cigarette smoke (SSCS)] exposure to cigarette smoke is known to damage the lungs, alter the immune system, and predispose individuals to the development of emphysema and lung cancer. Previous work from these laboratories has demonstrated that administration of aerosolized substance P (SP) was capable of protecting the pulmonary and immune systems from damage due to environmental toxicants (e.g. hydrocarbon exposures). In the present study, the effects of SP on SSCS exposure were examined. Treatment of mice exposed to SSCS with aerosolized SP prevented pathological cellular and functional changes in the lung as reflected by prevention of damage to airway basement membranes/endothelial cells and preservation of normal airway dynamic compliance. Further, SP treatment reduced and/or prevented the occurrence of micronuclei formation in cells isolated from mice exposed in vivo to SSCS (an indicator of DNA/genetic damage). Finally, in an experimental in vivo lung cancer model, SP therapy significantly reduced the numbers of lung tumors, increased animal survival, and activated pulmonary immune defense mechanisms. Thus, aerosolized SP therapy appears to be capable of inhibiting preventing and/or reversing the cellular and genetic precursors of emphysema and malignancy that often result from exposure to cigarette smoke.
Cell Mol Biol (Noisy-le-grand) 2003 Mar
PMID:Aerosolized substance P protects against cigarette-induced lung damage and tumor development. 1288 98


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