scholarly journals The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection

2007 ◽  
Vol 204 (8) ◽  
pp. 1901-1909 ◽  
Author(s):  
Charaf Benarafa ◽  
Gregory P. Priebe ◽  
Eileen Remold-O'Donnell
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Serine Proteases ◽  
Late Onset ◽  
Surfactant Protein ◽  
Cathepsin G ◽  
Intrinsic Defect ◽  
Surfactant Protein D ◽  
Bacterial Clearance ◽  
Cytokines And Chemokines ◽  
Molecular Components

Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa. On infection, wild-type (WT) and serpinb1-deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1−/− mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1-deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein–D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance in serpinb1−/− mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.

scholarly journals Clearance of Pseudomonas aeruginosa from a Healthy Ocular Surface Involves Surfactant Protein D and Is Compromised by Bacterial Elastase in a Murine Null-Infection Model

2009 ◽  
Vol 77 (6) ◽  
pp. 2392-2398 ◽  
Author(s):  
James J. Mun ◽  
Connie Tam ◽  
David Kowbel ◽  
Samuel Hawgood ◽  
Mitchell J. Barnett ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Ocular Surface ◽  
Surfactant Protein ◽  
Tear Fluid ◽  
Bacterial Invasion ◽  
Surfactant Protein D ◽  
Infection Model ◽  
Strain Pao1 ◽  
Corneal Epithelial

ABSTRACT Our previous studies showed that surfactant protein D (SP-D) is present in human tear fluid and that it can protect corneal epithelial cells against bacterial invasion. Here we developed a novel null-infection model to test the hypothesis that SP-D contributes to the clearance of viable Pseudomonas aeruginosa from the healthy ocular surface in vivo. Healthy corneas of Black Swiss mice were inoculated with 107 or 109 CFU of invasive (PAO1) or cytotoxic (6206) P. aeruginosa. Viable counts were performed on tear fluid collected at time points ranging from 3 to 14 h postinoculation. Healthy ocular surfaces cleared both P. aeruginosa strains efficiently, even when 109 CFU was used: e.g., <0.01% of the original inoculum was recoverable after 3 h. Preexposure of eyes to bacteria did not enhance clearance. Clearance of strain 6206 (low protease producer), but not strain PAO1 (high protease producer), was delayed in SP-D gene-targeted (SP-D−/−) knockout mice. A protease mutant of PAO1 (PAO1 lasA lasB aprA) was cleared more efficiently than wild-type PAO1, but this difference was negligible in SP-D−/− mice, which were less able to clear the protease mutant. Experiments to study mechanisms for these differences revealed that purified elastase could degrade tear fluid SP-D in vivo. Together, these data show that SP-D can contribute to the clearance of P. aeruginosa from the healthy ocular surface and that proteases can compromise that clearance. The data also suggest that SP-D degradation in vivo is a mechanism by which P. aeruginosa proteases could contribute to virulence.

scholarly journals Increased Surfactant Protein D Fails to Improve Bacterial Clearance and Inflammation inserpinB1−/−Mice

2012 ◽  
Vol 47 (6) ◽  
pp. 792-799 ◽  
Author(s):  
J. Michael Stolley ◽  
Dapeng Gong ◽  
Kalamo Farley ◽  
Picheng Zhao ◽  
Jessica Cooley ◽  
...  
Keyword(s):  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Bacterial Clearance

scholarly journals Genetic Association With Pseudomonas aeruginosa Acquisition in Cystic Fibrosis: Influence of Surfactant Protein D and Mannose-Binding Lectin

2021 ◽  
Vol 12 ◽  
Author(s):  
Nasenien Nourkami-Tutdibi ◽  
Klemens Freitag ◽  
Michael Zemlin ◽  
Erol Tutdibi
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genetic Variants ◽  
Serum Levels ◽  
Surfactant Protein ◽  
Mannose Binding Lectin ◽  
Surfactant Protein D ◽  
Risk Haplotype ◽  
Mannose Binding ◽  
Binding Lectin

Background:Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is associated with poor prognosis. Surfactant protein-D (SFTPD) and mannose-binding lectin (MBL) play a critical role in innate immunity and response to bacterial infections. We investigated serum levels and genetic variants of SFTPD and MBL in CF patients.Method: Thirty-five Caucasian patients homozygous for ΔF508del were genotyped for functional relevant polymorphisms within MBL2 (promoter−221 Y/X, codons 52, 54, and 57) and SFTPD genes (Met11Thr, Ala160Thr, and Ser270Thr). Serum levels of collectins, clinical characteristics, and PA status were correlated with genetic data.Results: Patients age, gender, and PA status did not affect MBL and SFTPD serum concentrations. MBL concentrations were correlated with MBL haplotypes. Patients with chronic Pseudomonas aeroginosa infection (PAC) and MBL insufficiency had a shorter interval between first PA infection and onset of PAC (0.01 vs. 4.6 years, p &lt; 0.04) as well as a lower median age at transition to PAC (9.8 vs. 16.4 years, p &lt; 0.03) compared to MBL sufficient patients with PAC. SFTPD serum level and FEV1% (Spearman r = −0.41, p &lt; 0.03) showed a negative correlation irrespective of PA infection status. The hazard ratio to PA acquisition was increased in carriers of the SFTPD haplotype 11Thr-160Ala-270Ser compared to carriers of the common 11Met-160Thr-270Ser haplotype [HR 3.0 (95%CI: 1.1–8.6), p &lt; 0.04].Conclusion: MBL insufficiency leads to a shorter interval between first PA infection and onset of chronic infection. Susceptibility to PA acquisition is associated with SFTPD genetic variants with 11Thr-160Ala-270Ser as risk haplotype for early PA infection. This may be due to presence of threonine associated with oligomeric structure of SFTPD and binding ability to bacteria.

scholarly journals Surfactant Protein D Is Present in Human Tear Fluid and the Cornea and Inhibits Epithelial Cell Invasion by Pseudomonas aeruginosa

2005 ◽  
Vol 73 (4) ◽  
pp. 2147-2156 ◽  
Author(s):  
Minjian Ni ◽  
David J. Evans ◽  
Samuel Hawgood ◽  
E. Margot Anders ◽  
Robert A. Sack ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Surfactant Protein ◽  
Tear Fluid ◽  
Surfactant Protein D ◽  
Bacteriostatic Activity ◽  
Corneal Epithelial Cells ◽  
Corneal Epithelial ◽  
Human And Mouse

ABSTRACT We have previously shown that human tear fluid protects corneal epithelial cells against Pseudomonas aeruginosa in vitro and in vivo and that protection does not depend upon tear bacteriostatic activity. We sought to identify the responsible tear component(s). The hypothesis tested was that collectins (collagenous calcium-dependent lectins) were involved. Reflex tear fluid was collected from healthy human subjects and examined for collectin content by enzyme-linked immunosorbent assay (ELISA) and Western blot with antibody against surfactant protein D (SP-D), SP-A, or mannose-binding lectin (MBL). SP-D, but not SP-A or MBL, was detected by ELISA of human reflex tear fluid. Western blot analysis of whole tears and of high-performance liquid chromatography tear fractions confirmed the presence of SP-D, most of which eluted in the same fraction as immunoglobulin A. SP-D tear concentrations were calculated at ∼2 to 5 μg/ml. Depletion of SP-D with mannan-conjugated Sepharose or anti-SP-D antibody reduced the protective effect of tears against P. aeruginosa invasion. Recombinant human or mouse SP-D used alone reduced P. aeruginosa invasion of epithelial cells without detectable bacteriostatic activity or bacterial aggregation. Immunofluorescence microscopy revealed SP-D antibody labeling throughout the corneal epithelium of normal, but not gene-targeted SP-D knockout mice. SP-D was also detected in vitro in cultured human and mouse corneal epithelial cells. In conclusion, SP-D is present in human tear fluid and in human and mouse corneal epithelia. SP-D is involved in human tear fluid protection against P. aeruginosa invasion. Whether SP-D plays other roles in the regulation of other innate or adaptive immune responses at the ocular surface, as it does in the airways, remains to be explored.

scholarly journals Surfactant Protein D Contributes to Ocular Defense against Pseudomonas aeruginosa in a Murine Model of Dry Eye Disease

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65797 ◽  
Author(s):  
Susan R. Heimer ◽  
David J. Evans ◽  
James J. Mun ◽  
Michael E. Stern ◽  
Suzanne M. J. Fleiszig
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Dry Eye ◽  
Murine Model ◽  
Surfactant Protein ◽  
Dry Eye Disease ◽  
Eye Disease ◽  
Surfactant Protein D

scholarly journals Potent and Broad but not Unselective Cleavage of Cytokines and Chemokines by Human Neutrophil Elastase and Proteinase 3

2020 ◽  
Vol 21 (2) ◽  
pp. 651 ◽  
Author(s):  
Zhirong Fu ◽  
Srinivas Akula ◽  
Michael Thorpe ◽  
Lars Hellman
Keyword(s):  
Mast Cell ◽  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Serine Proteases ◽  
General Pattern ◽  
Neutrophil Activation ◽  
Cathepsin G ◽  
Human Neutrophil Elastase ◽  
Proteinase 3 ◽  
Cytokines And Chemokines

In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including IL-18, TSLP and IL-33. To determine if this is a general pattern for many of the hematopoietic serine proteases we have analyzed the human neutrophil elastase (hNE) and human proteinase 3 (hPR-3) for their cleavage of a panel of 69 different human cytokines and chemokines. Our results showed that these two latter enzymes, in sharp contrast to the two previous, had a very potent and relatively unrestrictive cleavage on this panel of targets. Almost all of these proteins were cleaved and many of them were fully degraded. In light of the proteases abundance and their colocalization, it is likely that together they have a very potent degrading activity on almost any protein in the area of neutrophil activation and granule release, including both foreign bacterial or viral proteins as well as various self-proteins in the area of inflammation/infection. However, a few very interesting exceptions to this pattern were found indicating a high resistance to degradation of some cytokines and chemokines, including TNF-α, IL-5, M-CSF, Rantes, IL-8 and MCP-1. All of these are either important for monocyte-macrophage, neutrophil or eosinophil proliferation, recruitment and activation, suggesting that cytokines/chemokines and proteases may have coevolved to not block the recruitment of monocytes–macrophages, neutrophils and possibly eosinophils during an inflammatory response involving neutrophil activation.

The role of surfactant protein D in fibrotic lung remodelling

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
J Viereck ◽  
L Knudsen ◽  
JP Schneider ◽  
M Ochs ◽  
T Thum
Keyword(s):  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Lung Remodelling
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