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Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses  [cached]
Koga Hikari,Miyahara Nobuaki,Fuchimoto Yasuko,Ikeda Genyo
Respiratory Research , 2013, DOI: 10.1186/1465-9921-14-8
Abstract: Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.
Neutrophil Elastase Alters the Murine Gut Microbiota Resulting in Enhanced Salmonella Colonization  [PDF]
Navkiran Gill, Rosana B. R. Ferreira, L. Caetano M. Antunes, Benjamin P. Willing, Inna Sekirov, Fatimah Al-Zahrani, Martin Hartmann, B. Brett Finlay
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049646
Abstract: The intestinal microbiota has been found to play a central role in the colonization of Salmonella enterica serovar Typhimurium in the gastrointestinal tract. In this study, we present a novel process through which Salmonella benefit from inflammatory induced changes in the microbiota in order to facilitate disease. We show that Salmonella infection in mice causes recruitment of neutrophils to the gut lumen, resulting in significant changes in the composition of the intestinal microbiota. This occurs through the production of the enzyme elastase by neutrophils. Administration of recombinant neutrophil elastase to infected animals under conditions that do not elicit neutrophil recruitment caused shifts in microbiota composition that favored Salmonella colonization, while inhibition of neutrophil elastase reduced colonization. This study reveals a new relationship between the microbiota and the host during infection.
Inhibition of Human Neutrophil Elastase by Pentacyclic Triterpenes  [PDF]
Li Feng, Xiaoyu Liu, Weiliang Zhu, Fujiang Guo, YingchunWu, Rui Wang, Kaixian Chen, Cheng Huang, Yiming Li
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082794
Abstract: Scope Inhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat. Methods and Results An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 μM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity. Conclusion Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.
Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women
Mervat M El-Eshmawy, Eman H El-Adawy, Amany A Mousa, Amany E Zeidan, Azza A El-Baiomy, Elham R Abdel-Samie, Omayma M Saleh
BMC Women's Health , 2011, DOI: 10.1186/1472-6874-11-1
Abstract: Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. Measurements: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio.Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 ± 111.6 ng/ml) and normotensive (336.5 ± 81.5 ng/ml) obese women than in control non-obese women (243.9 ± 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC.Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population.The seventh report of the Joint National Committee (JNC-7) proposed a new classification distinguishing between individuals with normal blood pressure and established hypertension. The report categorized people with systolic blood pressure between 120 and 139 mm Hg or diastolic blood pressure between 80 and 89 mm Hg as having 'prehypertension' [1]. Data from t
Human neutrophil elastase and lung surfactant in acute respiratory distress syndrome
Blanco,Odalys; Lugones,Yuliannis; Gil,Dayrom F; Faure,Roberto; González,Yamilé;
Biotecnolog?-a Aplicada , 2009,
Abstract: human neutrophil elastase (hne) is one of the main proteases secreted into the alveolar space by infiltrated neutrophils during several inflammatory lung diseases such as cystic fibrosis, acute lung injury (ali) and acute respiratory distress syndrome (ards). consequently, a number of therapeutic approaches based on the specific inhibition of hne are currently under investigation. the present work reviews the physiopathological role of hne in ali/ards and its relationship to the pulmonary surfactant system, as well as the clinical potential of protease inhibitors in this setting. in spite of the complex physiopathology of these diseases, the available evidence points to a direct link between hne and ali/ards, with increased local concentrations of this protease in animal models of ali as well as in patients. furthermore, the unbalanced ratio of protease/endogenous inhibitors characteristic of these disorders has led to the pharmacological and clinical evaluation of hne inhibitors, examining their addition to currently available exogenous surfactant with promising results.
Glucocorticosteroids Differentially Regulate MMP-9 and Neutrophil Elastase in COPD  [PDF]
Ross Vlahos, Peter A. B. Wark, Gary P. Anderson, Steven Bozinovski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033277
Abstract: Background Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD. Methods Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated. Results Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation. Conclusions As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.
In Vitro Inhibition of Neutrophil Elastase Activity by Inhaled Anti-Pseudomonas Antibiotics Used in Cystic Fibrosis Patients  [PDF]
Andreas Hector,Matthias Kappler,Matthias Griese
Mediators of Inflammation , 2010, DOI: 10.1155/2010/809591
Abstract: Background. Inhaled antibiotics are commonly used in the treatment of cystic fibrosis lung disease. A previous study suggested neutrophil elastase activation by colistin in vitro. Here, we investigated direct effects of the commonly used antibiotics colistin and tobramycin on neutrophil elastase activity. Methods. Neutrophil elastase was measured spectrophotometrically. The antibiotics colistin and tobramycin were added in different concentrations with or without the addition of albumin. Results. Generally, neutrophil elastase activity was lower in the absence of albumin compared to its presence. Both antibiotics, colistin and tobramycin, had inhibitory effects on neutrophil elastase activity except for high concentrations of colistin when albumin was absent. Conclusions. Our results suggest inhibitory effects of colistin and tobramycin in vitro. There was a clear dependency of neutrophil elastase measurements on the presence of albumin. Clinical studies are needed to investigate potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways. 1. Background Cystic fibrosis is the most common recessive disease in Caucasians with a prevalence of about 1?:?2500 [1]. Cystic fibrosis is characterized by progressive lung destruction due to chronic neutrophilic airway inflammation and bacterial infection [2]. Most of the morbidity and mortality of cystic fibrosis patients results from the lung disease [3]. Large amounts of neutrophils are targeted into the airways, mostly by the chemokine interleukin 8, where they are primed, activated and engage bacterial phagocytosis releasing high amounts of oxidants and proteases [4]. Neutrophils derived from cystic fibrosis patients release significantly higher levels of neutrophil elastase when activated by interleukin 8 compared to healthy subjects or bronchiectatic patients [5]. It was suggested that neutrophils in cystic fibrosis airway environment undergo necrosis, rather than apoptosis [6, 7]. This leads to uncontrolled secretion of interleukin 8 with further chemotaxis and accumulation of neutrophils and an overwhelming release of neutrophil elastase. Collateral damage of airway surface epithelium and destruction of neighboring structures allow bacterial persistence in niches and further perpetuation of inflammation [8, 9]. With ongoing cystic fibrosis lung disease, a state termed as prolonged endobronchial protease activity (PEPA) is established [10]. We recently found that phagocytic activity is reduced in cystic fibrosis neutrophils supposedly due to proteolytic
Is neutrophil elastase the missing link between emphysema and fibrosis? Evidence from two mouse models
Monica Lucattelli, Barbara Bartalesi, Eleonora Cavarra, Silvia Fineschi, Benedetta Lunghi, Piero A Martorana, Giuseppe Lungarella
Respiratory Research , 2005, DOI: 10.1186/1465-9921-6-83
Abstract: This study was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (BLM) or by chronic exposure to cigarette-smoke. In order to assess the protease-dependence of the BLM-induced lesion, a group mice was treated with 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine proteinase inhibitor active toward neutrophil elastase. Lungs from each experimental group were used for the immunohistochemical assessment of transforming growth factor-β (TGF-β) and transforming growth factor-α (TGF-α) and for determination of the mean linear intercept as well as the percent volume densities of fibrosis and of emphysematous changes. Additionally, the lungs were also assessed for desmosine content and for the determination of elastase levels in the pulmonary interstitium by means of immunoelectron microscopy.We demonstrate that in BLM-treated mice (i) the development of elastolytic emphysema precedes that of fibrosis; (ii) significant amount of elastase in alveolar interstitium is associated with an increased expression of TGF-β and TGF-α; and finally, (iii) emphysematous and fibrotic lesions can be significantly attenuated by using a protease inhibitor active against neutrophil elastase.Also, in a strain of mice that develop both emphysema and fibrosis after chronic cigarette-smoke exposure, the presence of elastase in alveolar structures is associated with a positive immunohistochemical reaction for reaction for both TGF-β and TGF-α.The results of the present study strongly suggest that neutrophil elastase may represent a common pathogenic link between emphysema and fibrosis. Proteases and in particular neutrophil elastase could act as regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells resulting either in emphysema or in fibrosis or both.Lung emphysema and fibrosis are generally considered to be two diseases that totally differ in their morphological aspects and pathogenic mechan
Solar Ultraviolet Irradiation Induces Decorin Degradation in Human Skin Likely via Neutrophil Elastase  [PDF]
Yong Li, Wei Xia, Ying Liu, Henriette A. Remmer, John Voorhees, Gary J. Fisher
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072563
Abstract: Exposure of human skin to solar ultraviolet (UV) irradiation induces matrix metalloproteinase-1 (MMP-1) activity, which degrades type I collagen fibrils. Type I collagen is the most abundant protein in skin and constitutes the majority of skin connective tissue (dermis). Degradation of collagen fibrils impairs the structure and function of skin that characterize skin aging. Decorin is the predominant proteoglycan in human dermis. In model systems, decorin binds to and protects type I collagen fibrils from proteolytic degradation by enzymes such as MMP-1. Little is known regarding alterations of decorin in response to UV irradiation. We found that solar-simulated UV irradiation of human skin in vivo stimulated substantial decorin degradation, with kinetics similar to infiltration of polymorphonuclear (PMN) cells. Proteases that were released from isolated PMN cells degraded decorin in vitro. A highly selective inhibitor of neutrophil elastase blocked decorin breakdown by proteases released from PMN cells. Furthermore, purified neutrophil elastase cleaved decorin in vitro and generated fragments with similar molecular weights as those resulting from protease activity released from PMN cells, and as observed in UV-irradiated human skin. Cleavage of decorin by neutrophil elastase significantly augmented fragmentation of type I collagen fibrils by MMP-1. Taken together, these data indicate that PMN cell proteases, especially neutrophil elastase, degrade decorin, and this degradation renders collagen fibrils more susceptible to MMP-1 cleavage. These data identify decorin degradation and neutrophil elastase as potential therapeutic targets for mitigating sun exposure-induced collagen fibril degradation in human skin.
Neutrophil Elastase Causes Tissue Damage That Decreases Host Tolerance to Lung Infection with Burkholderia Species  [PDF]
Manoranjan Sahoo equal contributor,Laura del Barrio equal contributor,Mark A. Miller,Fabio Re
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004327
Abstract: Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and causes melioidosis. We have recently shown that inflammasome-triggered pyroptosis and IL-18 are equally important for resistance to B. pseudomallei, whereas IL-1β is deleterious. Here we show that the detrimental role of IL-1β during infection with B. pseudomallei (and closely related B. thailandensis) is due to excessive recruitment of neutrophils to the lung and consequent tissue damage. Mice deficient in the potentially damaging enzyme neutrophil elastase were less susceptible than the wild type C57BL/6J mice to infection, although the bacterial burdens in organs and the extent of inflammation were comparable between C57BL/6J and elastase-deficient mice. In contrast, lung tissue damage and vascular leakage were drastically reduced in elastase-deficient mice compared to controls. Bradykinin levels were higher in C57BL/6 than in elastase-deficient mice; administration of a bradykinin antagonist protected mice from infection, suggesting that increased vascular permeability mediated by bradykinin is one of the mechanisms through which elastase decreases host tolerance to melioidosis. Collectively, these results demonstrate that absence of neutrophil elastase increases host tolerance, rather than resistance, to infection by minimizing host tissue damage.
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