Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the content and molecular state of secretory leukocyte protease inhibitor (SLPI) in the airways in chronic airway diseases were studied. SLPI in bronchoalveolar and bronchial lavage fluids (BALF and BLF) from normal subjects and patients with diffuse panbronchiolitis (DPB), and in mucoid sputa from patients with emphysema and in purulent sputa from DPB patients were examined by ELISA and Western blotting. Results showed that in the BALF and BLF of normal subjects, the SLPI/alpha 1-protease inhibitor (alpha 1-PI) ratios (M/M) are about 0.6 and 6, respectively and the neutrophil elastase inhibitory capacity of BLF is mainly due to SLPI. In the BALF and BLF of DPB patients, both the elastase activity and alpha 1-PI level are increased, but the SLPI level is decreased. In purulent sputa, the elastase activity was found to be 430-fold that in mucoid sputa and the alpha 1-PI level to be 3.5-fold that in mucoid sputa, but the SLPI level was slightly lower in the mucoid sputa. Analysis by Western blotting showed that in BLF from normal subjects and mucoid sputa, SLPI is present in an intact form and in complexes with other substances, whereas in BLF and purulent sputa from DPB patients, SLPI is present in a degraded form and in complexes with other substances, but not in the intact form. These results indicate that SLPI is the main protease inhibitor in the airways of both normal subjects and patients with hypersecretory respiratory diseases without infection, but that its level is insufficient to overcome the increased protease burden in the airways of DPB patients.
 ...
PMID:Analysis of secretory leukocyte protease inhibitor (SLPI) in bronchial secretions from patients with hypersecretory respiratory diseases. 810 62

Alpha-1-antitrypsin deficiency is a common, underrecognized disorder manifested by emphysema in adults and liver disease in children. Early diagnosis and subsequent prevention of lung inflammation due to cigarette smoking, infection, and airborne irritants form the most rational approach to slow the progression of the lung destruction associated with alpha 1AT deficiency. Currently, liver transplantation is the only therapy available to patients with severe liver disease due to alpha 1AT deficiency. Less commonly, many inflammatory and/or immune-mediated diseases have been described in association with alpha 1AT deficiency. These observations are probably related to the role that alpha 1AT plays in the immune response both as a target for modulation by cytokines and as a modulator of the immune response. At present, therapy for the emphysema associated with alpha 1AT is limited to weekly augmentation therapy with recombinant alpha 1AT. Future therapeutic modalities include aerosol alpha 1AT, secretory leukocyte proteinase inhibitor, low molecular weight inhibitors of neutrophil elastase, and gene transfer via viral vector.
 ...
PMID:Clinical features and molecular characteristics of alpha 1-antitrypsin deficiency. 810

Chronic inflammation containing CD8(+) lymphocytes, neutrophils, and macrophages, and pulmonary emphysema coexist in lungs from patients with chronic obstructive pulmonary disease. Although this inflammatory response is believed to cause the remodeling that is seen in these tissues, the mechanism(s) by which inflammation causes emphysema have not been defined. Here we demonstrate that interferon gamma (IFN-gamma), a prominent product of CD8(+) cells, causes emphysema with alveolar enlargement, enhanced lung volumes, enhanced pulmonary compliance, and macrophage- and neutrophil-rich inflammation when inducibly targeted, in a transgenic fashion, to the adult murine lung. Prominent protease and antiprotease alterations were also noted in these mice. They included the induction and activation of matrix metalloproteinase (MMP)-12 and cathepsins B, H, D, S, and L, the elaboration of MMP-9, and the selective inhibition of secretory leukocyte proteinase inhibitor. IFN-gamma causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues.
 ...
PMID:Interferon gamma induction of pulmonary emphysema in the adult murine lung. 1110 1

Secretory leukocyte protease inhibitor (SLPI) is a potent inhibitor of human leukocyte elastase. In some chronic airway diseases, the level of SLPI is decreased in sputum, leading to the continuation of neutrophil inflammation. In this study, the role of SLPI in subclinical pulmonary emphysema was examined. Sequential bronchoalveolar lavage was performed in an attempt to separately evaluate the levels of SLPI in the large airways and in the peripheral airways for two groups of smokers. One group had subclinical emphysema by computed-tomography scans and one group did not. SLPI localized in alveolar macrophages (AM) was also assessed. The level of SLPI was significantly elevated in the peripheral airways from the subjects with emphysema compared to those without emphysema (1589.2+/-353.9 versus 729.1+/-31.0 ng x mL(-1)), although it was similar in the large airways (3442.3+/-499.6 versus 2535.7+/-578.8 ng x mL(-1)). There was a trend for higher amount of SLPI to be released from AM in subjects with subclinical emphysema, although this did not reach statistical significance. In conclusion, there is compensatory upregulation of secretory leukocyte protease inhibitor in peripheral airways in subclinical pulmonary emphysema, which is in sharp contrast to the decreased level of secretory leukocyte protease inhibitor reported in some chronic airway diseases.
 ...
PMID:Role of secretory leukocyte protease inhibitor in the development of subclinical emphysema. 1210 56

Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1alpha/CCL-3 (MIP-1alpha/CCL-3), MIP-1beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.
 ...
PMID:Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema. 1628 50

Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN-gamma and interleukin (IL)-13, respectively, both caused emphysema. The IFN-gamma response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI). Interestingly, IFN-gamma induced its destructive effects via at least two mechanisms, a CCR5/cathepsin-dependent and apoptosis-mediated pathway and an MMP-12-dependent/apoptosis-independent pathway. CS-induced inflammation, apoptosis, and emphysema were also induced by IFN-gamma- and CCR5-dependent mechanisms. In contrast, IL-13-induced emphysema was associated with eosinophilia, mucus metaplasia, and pulmonary fibrosis. In this setting, IL-13 stimulated MMPs, cathepsins, and a variety of CC chemokines while inhibiting alpha(1)-antitrypsin. A cathepsin-dependent apoptosis pathway also contributed to this remodeling response. Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF(165) excess producing an asthmalike pulmonary response and IFN-gamma abrogating this response while inducing emphysematous alveolar destruction. These findings provide molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between asthma and COPD. They also highlight the complexity of the pathways that can induce alveolar destruction and suggest that there is a continuum, based on VEGF, between asthma and COPD.
 ...
PMID:State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice. 1692 Nov 26

Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.
 ...
PMID:Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. 2084 4


<< Previous 1 2