Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The underlying mechanism involved in the interaction between neutrophil elastase inhibitors and tachykinins has not been elucidated. In this study we have examined the effects of sivelestat, a neutrophil elastase inhibitor, on the in vitro responses of airways from lipopolysaccharide (LPS)-untreated or -treated guinea-pigs to substance P. Substance P (0.01-30 micromol/l) produced concentration-dependent contractions of both tracheal and bronchial ring preparations of LPS-untreated or -treated guinea-pigs. Responsiveness to substance P in these isolated airway preparations was augmented by either epithelium removal or LPS treatment. In epithelium-intact tracheal ring preparations isolated from LPS-untreated guinea-pigs, sivelestat (100 micromol/l) significantly inhibited substance P-induced contractions. The inhibitory action was markedly attenuated by pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l), and was almost undetected following removal of the epithelium. On the other hand, in bronchial ring preparations isolated from LPS-untreated guinea-pigs, sivelestat had only a very slight effect on substance P-induced contraction of the epithelium-intact preparation, whereas sivelestat greatly inhibited contraction in epithelium-removed bronchial ring preparations. In LPS-treated guinea-pigs, whether the epithelium was intact or not, sivelestat significantly inhibited the substance P-induced contraction of bronchial ring preparations. Pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l) did not affect the inhibitory effect of sivelestat in bronchial ring preparations. In conclusion, epithelium removal or LPS treatment induced hyperreactivity to substance P in the guinea-pig airway. Sivelestat caused epithelium-, nitric oxide- and prostaglandin-dependent inhibition of the substance P-induced contraction of isolated guinea-pig tracheal ring preparations. In contrast, the inhibitory effect of sivelestat on substance P-induced contraction of guinea-pig bronchial ring preparations is mediated by epithelium-, nitric oxide- and prostaglandin-independent mechanisms. Sivelestat may be effective in reducing the airway hyperresponsiveness to tachykinins induced by epithelial injury as occurs in LPS-mediated inflammatory lung diseases.
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PMID:Epithelium-dependent and -independent inhibitory effects of sivelestat, a neutrophil elastase inhibitor, on substance P-induced contraction of airway smooth muscle in lipopolysaccharide-treated guinea-pigs. 1642 65

Damage to the lung microcirculation and alveoli caused by activated leukocytes is known to play an important role in the development of acute lung injury (ALI). The aim of this study is to evaluate the difference in the effect of pretreatment and posttreatment of a synthetic neutrophil elastase inhibitor sivelestat on ALI. Hamsters were instilled with 10.0 mg/kg of lipopolysaccharide (LPS) intratracheally for 1 h to simulate ALI. Two milligrams per kilogram of sivelestat was injected intraperitoneally either previously or after LPS infusion. One and 24 hours after the infusion of LPS, pulmonary microcirculation was observed under the intravital microscopy. In another series, the blood cell counts were evaluated. The adhesive leukocyte count on the endothelium was significantly lower in pretreatment group compared with control group (P < 0.01), whereas the difference was not significant in the posttreatment group. Similarly, the number of obstructed capillary was significantly lower in the pretreatment group (P < 0.01). The width of interstitium was significantly lower in the pretreatment and posttreatment group (P < 0.01 and 0.05, respectively). A comparison of white blood cell counts showed a better maintenance in pretreatment group (P < 0.05). Pretreatment of sivelestat demonstrated a protective effect on both intravascular and extravascular damage in the lung, whereas posttreatment only suppressed the latter damage.
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PMID:Pretreatment of sivelestat sodium hydrate improves the lung microcirculation and alveolar damage in lipopolysaccharide-induced acute lung inflammation in hamsters. 1678 4

Stimuli-induced expression of certain mucin genes has been demonstrated to occur as a result of ligand-dependent activation of the epidermal growth factor receptor (EGFR). In particular, MUC5AC expression can be induced by cigarette-smoke, neutrophil elastase and lipopolysaccharide (LPS) following activation of tumour necrosis factor alpha-converting enzyme. We now show that a large of number of stimuli relevant to the cystic fibrosis lung - neutrophil elastase, LPS, Pam3Cys-Ser-(Lys)4 Hydrochloride (a lipopeptide analogue), CpG DNA (which mimics bacterial DNA) and cystic fibrosis bronchoalveolar lavage fluid - can activate MUC1 and 2 expression as well as MUC5AC expression in lung epithelial cells via an EGFR-dependent mechanism. In addition, we demonstrate that the immunomodulatory anti-protease, secretory leucoprotease inhibitor, can inhibit stimuli-induced MUC1, 2 and 5AC expression via a mechanism that is primarily dependent on the inhibition of transforming growth factor type alpha release. Therefore, mucin gene expression, induced by cystic fibrosis respiratory stimuli, can be inhibited by secretory leucoprotease inhibitor indicating its potential importance as an anti-mucin agent in cystic fibrosis and other chronic lung diseases characterized by mucus hypersecretion.
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PMID:Effect of pro-inflammatory stimuli on mucin expression and inhibition by secretory leucoprotease inhibitor. 1702 78

To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a method of quantifying intracellular human neutrophil elastase (HNE) in lysed sputum polymorphs as a means to study the degranulation status of LPS-recruited neutrophils. Induced sputum, blood and exhaled nitric oxide (NO) were collected from 10 healthy non-atopic human subjects after inhaling a single 15 microg dose of Escherichia coil LPS in an open study. At 6 hours, LPS inhalation caused significant increase of sputum and blood neutrophils but without parallel increase in myeloperoxidase, HNE or interleukin-8 (IL-8) in sputum sol and blood, or exhaled NO. Intracellular HNE in lysed sputum polymorphs or purified blood neutrophils did not show any significant changes between inhaled LPS and saline, nor was there any appreciable change in percentage HNE release induced by N-Formyl-Met-Leu-Phe (fMLP) in vitro. We concluded that in healthy humans, the transient neutrophilic inflammation induced by a single dose of inhaled 15 microg LPS is mainly characterized by cell recruitment, not enhanced secretion of granular mediators or increased exhaled NO based on our experimental conditions.
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PMID:Lack of neutrophil degranulation in low-dose endotoxin inhalation based on a novel intracellular assay. 1713 81

Proteolytic processing of laminin-332 by matrix metalloproteinase (MMP)-2 and MMP-14 has been shown to yield fragments that are promigratory for epithelial cells. During acute and chronic inflammation, proteases are elaborated by neutrophils and macrophages that can degrade basement membranes. We investigated the susceptibility of laminin-332 to degradation by the following neutrophil and macrophage proteases: neutrophil elastase (NE), cathepsin G, proteinase-3, and MMPs-2, -8, -9, and -12. Protease-specific differences were seen in the capacity to cleave the individual chains of laminin-332. NE and MMP-12 showed the greatest activity toward the gamma2 chain, generating a fragment similar in size to the gamma2x fragment generated by MMP-2. The digestion pattern of laminin-332 by degranulated neutrophils was nearly identical to that generated with NE alone. Digestion by supernatants of degranulated neutrophils was blocked by an inhibitor of NE, and NE-deficient neutrophils were essentially unable to digest laminin-332, suggesting that NE is the major neutrophil-derived protease that degrades laminin-332. In vivo, laminin gamma2 fragments were found in the bronchoalveolar lavage fluid of wild-type mice treated with lipopolysaccharide, whereas that obtained from NE-deficient mice showed a different cleavage pattern. In addition, NE cleaved a synthetic peptide derived from the region of human laminin gamma2 containing the MMP-2 cleavage site, suggesting that NE may generate laminin-332 fragments that are also promigratory. Both laminin-332 fragments generated by NE digestion and NE-digested laminin gamma2 peptide were found to be chemotactic for neutrophils. Collectively, these data suggest that degradation of laminin-332 by NE generates fragments with important biological activities.
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PMID:Neutrophil elastase cleaves laminin-332 (laminin-5) generating peptides that are chemotactic for neutrophils. 1817 64

1. Sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, is used to treat acute lung injury associated with systemic inflammatory response syndrome, but its effects have not been described for endotoxaemia. In the present study, we examined the effects of a continuous infusion of sivelestat on intestinal mechanical activity and blood pressure using an endotoxaemic model in conscious, unrestrained guinea-pigs. 2. Guinea-pigs underwent laparotomy while anaesthetized and were implanted with a force transducer sutured onto the taenia caecum. With this transducer, changes in tension in the intestinal longitudinal muscle were measured continuously via telemetry. Catheters were inserted into the carotid artery and jugular vein, were tunnelled subcutaneously and were accessed from the back of the neck. These catheters were connected to a cannula swivel and were used to monitor arterial pressure as well as to administer drugs i.v. in conscious, unrestrained guinea-pigs. Twenty hours after surgery, guinea-pigs received a single dose of lipopolysaccharide (LPS; 0.3 mg/kg, i.p.) 10 min after the start of a continuous 2 h i.v. infusion of sivelestat (30 mg/kg per h) or vehicle (saline). Elastase activity before and after sivelestat or vehicle administration was measured spectrometrically using a specific synthetic substrate. 3. We confirmed that intestinal longitudinal muscle tension decreased 2-3 h after LPS administration in the control group, with a concurrent decline in blood pressure. In guinea-pigs treated with sivelestat, the LPS-induced decreases in muscle tension and blood pressure were significantly reduced. In LPS-treated control guinea-pigs, serum elastase activity was elevated and this increase was significantly attenuated by administration of sivelestat. 4. The findings from the present study suggest that sivelstat can effectively reduce intestinal dysfunction and attenuate LPS-induced decreases in blood pressure in endotoxaemia.
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PMID:Continuous infusion of sivelestat sodium hydrate prevents lipopolysaccharide-induced intestinal paralysis and hypotension in conscious guinea-pigs. 1834 72

Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis. The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, inducible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-kappaB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-kappaB activity.
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PMID:A neutrophil elastase inhibitor, sivelestat, reduces lung injury following endotoxin-induced shock in rats by inhibiting HMGB1. 1853 84

Elafin is a neutrophil serine protease inhibitor expressed in lung and displaying anti-inflammatory and anti-bacterial properties. Previous studies demonstrated that some innate host defense molecules of the cystic fibrosis (CF) and chronic obstructive pulmonary disease airways are impaired due to increased proteolytic degradation observed during lung inflammation. In light of these findings, we thus focused on the status of elafin in CF lung. We showed in the present study that elafin is cleaved in sputum from individuals with CF. Pseudomonas aeruginosa-positive CF sputum, which was found to contain lower elafin levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective in cleaving recombinant elafin. NE plays a pivotal role in the process as only NE inhibitors are able to inhibit elafin degradation. Further in vitro studies demonstrated that incubation of recombinant elafin with excess of NE leads to the rapid cleavage of the inhibitor. Two cleavage sites were identified at the N-terminal extremity of elafin (Val-5-Lys-6 and Val-9-Ser-10). Interestingly, purified fragments of the inhibitor (Lys-6-Gln-57 and Ser-10-Gln-57) were shown to still be active for inhibiting NE. However, NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination. In conclusion, this study provides evidence that elafin is cleaved by its cognate enzyme NE present at excessive concentration in CF sputum and that P. aeruginosa infection promotes this effect. Such cleavage may have repercussions on the innate immune function of elafin.
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PMID:Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. 1879 64

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used in Japan as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation (DIC), shock, and pancreatitis. Recent in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties beyond their inhibition of neutrophil elastase at the site of inflammation. However, the therapeutic effects of UTI in vivo remain unclear. In this review, we introduce the roles of UTI in the experimental systemic inflammatory response induced by both intraperitoneal and intratracheal administration of lipopolysaccharide using UTI deficient and wild-type mice. Our experiments suggest that UTI can protect against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly, through the inhibition of proinflammatory cytokine and chemokine expression. UTI may therefore present an attractive "rescue" therapeutic option for systemic inflammatory response syndromes such as DIC, acute lung injury, and multiple organ dysfunction.
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PMID:Protective effects of urinary trypsin inhibitor on systemic inflammatory response induced by lipopolysaccharide. 1901 47

Periodontitis is a bacterium-induced chronic inflammation that destroys tissues that attach teeth to jaw bone. Pathologically excessive matrix metalloproteinase 8 (MMP-8) is among the key players in periodontal destruction by initiating type I collagen degradation. We studied MMP-8 in Porphyromonas gingivalis-induced periodontitis by using MMP-8-deficient (MMP8(-/-)) and wild-type (WT) mice. Alveolar bone loss, inflammatory mediator expression, serum immunoglobulin, and lipoprotein responses were investigated to clarify the role of MMP-8 in periodontitis and systemic inflammatory responses. P. gingivalis infection induced accelerated site-specific alveolar bone loss in both MMP8(-/-) and WT mice relative to uninfected mice. The most extensive bone degradation took place in the P. gingivalis-infected MMP8(-/-) group. Surprisingly, MMP-8 significantly attenuated (P < 0.05) P. gingivalis-induced site-specific alveolar bone loss. Increased alveolar bone loss in P. gingivalis-infected MMP8(-/-) and WT mice was associated with increase in gingival neutrophil elastase production. Serum lipoprotein analysis demonstrated changes in the distribution of high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL) particles; unlike the WT mice, the MMP8(-/-) mice underwent a shift toward a smaller HDL/VLDL particle sizes. P. gingivalis infection increased the HDL/VLDL particle size in the MMP8(-/-) mice, which is an indicator of lipoprotein responses during systemic inflammation. Serum total lipopolysaccharide activity and the immunoglobulin G-class antibody level in response to P. gingivalis were significantly elevated in both infected mice groups. Thus, MMP-8 appears to act in a protective manner inhibiting the development of bacterium-induced periodontal tissue destruction, possibly through the processing anti-inflammatory cytokines and chemokines. Bacterium-induced periodontitis, especially in MMP8(-/-) mice, is associated with systemic inflammatory and lipoprotein changes that are likely involved in early atherosclerosis.
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PMID:Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis. 1902


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