scholarly journals Neutrophil elastase promotes macrophage cell adhesion and cytokine production through the integrin-Src kinases pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Karina Krotova ◽  
Nazli Khodayari ◽  
Regina Oshins ◽  
George Aslanidi ◽  
Mark L. Brantly
Keyword(s):  
Neutrophil Elastase ◽  
Cytokine Production ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Src Kinase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Active Matrix ◽  
Physiological Processes ◽  
Signaling Activation

Abstract There are a number of respiratory diseases characterized by the presence of excess neutrophil elastase (NE) activity in tissues, including cystic fibrosis and chronic obstructive pulmonary disease (COPD). NE is considered a primary contributor to disease development, but the precise mechanism has yet to be fully determined. We hypothesized that NE alters the function of macrophages (Mɸ) which play a critical role in many physiological processes in healthy lungs. We demonstrate that monocyte-derived Mɸ exposed to NE releases active matrix metalloproteinases (MMPs), increase expression of pro-inflammatory cytokines TNFα, IL-1β, and IL-8, and reduce capacity to phagocytose bacteria. Changes in Mɸ function following NE treatment were accompanied by increased adhesion and cytoskeleton re-arrangement, indicating the possibility of integrin involvement. To support this observation, we demonstrate that NE induces phosphorylation of kinases from the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of Mɸ with a specific Src kinase inhibitor, PP2 completely prevents NE-induced pro-inflammatory cytokine production. Taken together these findings indicate that NE participates in lung destruction not only through direct proteolytic degradation of matrix proteins, but also through activation of Mɸ inflammatory and proteolytic functions.

scholarly journals Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5344
Author(s):  
Darren Leahy ◽  
Cameron Grant ◽  
Alex Jackson ◽  
Alex Duff ◽  
Nicholas Tardiota ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Critical Role ◽  
Methionine Sulfoxide ◽  
Chronic Obstructive ◽  
Human Neutrophil Elastase ◽  
Obstructive Pulmonary Disease ◽  
Methionine Residue ◽  
Methionine Sulfone

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase “super substrates” that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.

scholarly journals Neutrophil Elastase Activates Macrophage MMPs, Promotes Cell Adhesion and Cytokine Production Via Integrin-Src Kinases Pathway

2018 ◽  
Author(s):  
Karina Krotova ◽  
Nazli Khodayari ◽  
Regina Oshins ◽  
George Aslanidi ◽  
Mark L. Brantly
Keyword(s):  
Proteolytic Activity ◽  
Inflammatory Cytokines ◽  
Neutrophil Elastase ◽  
Cytokine Production ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Pathological Process ◽  
Tissue Destruction ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Pro Inflammatory Cytokines

ABSTRACTThere are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues including cystic fibrosis and alpha-1-antitrypsin deficiency induced lung destruction. It is generally accepted that NE actively contributes to this pathological process, but the precise mechanisms has yet to be determined. We hypothesized that NE activates the macrophages (M□) pro-inflammatory program. We demonstrate that following NE exposure, monocyte-derived M□ release proteolytic activity composed of several matrix metalloproteinases (MMPs) which could contribute to extracellular matrix (ECM) degradation. NE upregulates expression of M□ derived pro-inflammatory cytokines including TNFα, IL-1β, and IL-8. Thus, NE-activated M□ can contribute to tissue destruction through the proteolytic activity of metalloproteinases and by supporting chronic inflammation through expression of pro-inflammatory cytokines. We also demonstrate that NE increases M□ adhesion that is attenuated by antibodies specific to integrin subunits. We show that the effects of NE on M□ can be mediated through an activation of integrin pathways. In support of integrin involvement, we demonstrate that NE activates the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of macrophages with a specific Src kinase inhibitor, PP2, completely prevents NE-induced inflammatory cytokine production. Taken together these findings indicate that NE has effect on lung destruction that extends beyond direct proteolytic degradation of matrix proteins.

scholarly journals Exposure to the gut microbiota from cigarette smoke-exposed mice exacerbates cigarette smoke extract-induced inflammation in zebrafish larvae

2021 ◽  
Author(s):  
Simone Morris ◽  
Kathryn Wright ◽  
Vamshikrishna Malyla ◽  
Warwick J Britton ◽  
Philip M Hansbro ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Gut Microbiota ◽  
Cigarette Smoke ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Zebrafish Larvae ◽  
Modifying Factors ◽  
Physiological Processes ◽  
Inflammatory Phenotype

AbstractCigarette smoke (CS)-induced inflammation leads to a range of diseases including chronic obstructive pulmonary disease and cancer. Environmental factors including gut microbiota make up are major modifying factors that determine the severity of cigarette smoke-induced pathology. Adult zebrafish display increased inflammatory cytokine transcription when exposed to cigarette smoke extract (CSE) but incongruously do not produce a mucosal leukocytic inflammation phenotype. Zebrafish embryos and larvae have been used to model the effects of cigarette smoking on a range of physiological processes and offer an amenable platform for screening modifiers of cigarette smoke-induced pathologies. Here we exposed zebrafish larvae to CSE and showed that it was toxic and we characterised a CSE-induced leukocytic inflammatory phenotype with increased neutrophilic and macrophage responses. The CSE-induced phenotype was exacerbated by co-exposure to microbiota from the faeces of CS-exposed mice, but not control mice. Microbiota could be recovered from the gut of zebrafish and studied in isolation. This demonstrates the utility of the zebrafish-CSE exposure platform for identifying environmental modifiers of cigarette smoking-associated pathology and demonstrates that the CS-exposed mouse gut microbiota potentiates the inflammatory effects of CSE across host species.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

Allyl isothiocyanate upregulates MRP1 expression through Notch1 signaling in human bronchial epithelial cells

2020 ◽  
Vol 98 (5) ◽  
pp. 324-331
Author(s):  
Ni-ni Li ◽  
Yan Guo ◽  
Cheng-jun Jiang ◽  
Yuan-yuan Zhou ◽  
Chen-hui Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Allyl Isothiocyanate ◽  
Chronic Obstructive ◽  
Therapeutic Effects ◽  
Mobility Shift ◽  
Obstructive Pulmonary Disease ◽  
Suppression Effect ◽  
Notch1 Signaling ◽  
Mrp1 Expression

Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC.

Increased IL-33 expression in chronic obstructive pulmonary disease

2015 ◽  
Vol 308 (7) ◽  
pp. L619-L627 ◽  
Author(s):  
Jie Xia ◽  
Junling Zhao ◽  
Jin Shang ◽  
Miao Li ◽  
Zhilin Zeng ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Cell Activation ◽  
Critical Role ◽  
Serum Levels ◽  
Peripheral Blood Lymphocytes ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Interleukin 33 ◽  
Cellular Source

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by inflammatory cell activation and the release of inflammatory mediators. Interleukin-33 (IL-33) plays a critical role in various inflammatory and immunological pathologies, but evidence for its role in COPD is lacking. This study aimed to investigate the expression of IL-33 in COPD and to determine whether IL-33 participates in the initiation and progression of COPD. Levels of serum IL-33 and its receptors were measured by ELISA, and serum levels of IL-33, ST2, and IL-1 receptor accessory protein were elevated in patients with COPD compared with control subjects. Flow cytometry analysis further demonstrated an increase in peripheral blood lymphocytes (PBLs) expressing IL-33 in patients with COPD. Immunofluorescence analysis revealed that the main cellular source of IL-33 in lung tissue was human bronchial epithelial cells (HBEs). Cigarette smoke extract and lipopolysaccharide could enhance the ability of PBLs and HBEs to express IL-33. Furthermore, PBLs from patients with COPD showed greater IL-33 release in response to the stimulus. Collectively, these findings suggest that IL-33 expression levels are increased in COPD and related to airway and systemic inflammation. Therefore, IL-33 might contribute to the pathogenesis and progression of this disease.

Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing

2012 ◽  
Vol 113 (10) ◽  
pp. 1594-1603 ◽  
Author(s):  
Ioanna Sigala ◽  
Panayiotis Zacharatos ◽  
Stavroula Boulia ◽  
Dimitris Toumpanakis ◽  
Tatiana Michailidou ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytokine Production ◽  
Chronic Obstructive ◽  
No Production ◽  
Sham Operation ◽  
Concurrent Administration ◽  
No Donor ◽  
Obstructive Pulmonary Disease ◽  
Resistive Breathing ◽  
Synthase Inhibitor

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1β levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.

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