Secretory Leukocyte Protease Inhibitor Concentrations Research Articles

Salivary concentrations of secretory leukocyte protease inhibitor and matrix metallopeptidase-9 following a single bout of exercise are associated with intensity and hydration status.

To investigate the effects of exercise on salivary concentrations of inflammatory markers by analyzing a panel of 25 inflammatory markers in subjects who had participated in bicycle ergometer tests varying in workload and hydration status. Fifteen healthy young men (20-35 years) had performed 4 different exercise protocols of 1 hour duration in a randomly assigned cross-over design, preceded by a rest protocol. Individual workloads depended on participant's pre-assessed individual maximum workload (Wmax): rest (protocol 1), 70% Wmax in hydrated (protocol 2) and dehydrated (protocol 3) state, 50% Wmax (protocol 4) and intermittent 85%/55% Wmax in 2 min blocks (protocol 5). Saliva samples were collected before (T0) and immediately after exercise (T1), and at several time points after exercise (2 hours (T3), 3 hours (T4), 6 hours (T5) and 24 hours (T6)). Secretory Leukocyte Protease Inhibitor (SLPI), Matrix Metallopeptidase-9 (MMP-9) and lactoferrin was analyzed using a commercial ELISA kit, a panel of 22 cytokines and chemokines were analyzed using a commercial multiplex immunoassay. Data was analyzed using a multilevel mixed linear model, with multiple test correction. Among a panel of 25 inflammatory markers, SLPI concentrations were significantly elevated immediately after exercise in all protocols compared to rest and higher concentrations reflected the intensity of exercise and hydration status. MMP-9 showed a significant increase in the 70% Wmax dehydrated, 50% Wmax and intermittent protocols. Salivary concentrations of SLPI and MMP-9 seem associated with exercise intensity and hydration status and may offer non-invasive biomarkers to study (local) inflammatory responses to different exercise intensities in human studies.

Afterbirth oral fluid secretory leukocyte protease inhibitor decreased in acute histologic chorioamnionitis in preterm birth.

Secretory leukocyte protease inhibitor (SLPI) is an innate anti-inflammatory and anti-microbial peptide and produced in amnion of fetal membranes during pregnancy. However, studies on the association between SLPI levels in amniotic fluid and acute chorioamnionitis are limited. Afterbirth oral fluid (AOF) of the baby could be useful for representing the intra-amniotic environment precisely just before delivery. This study aimed to determine the relationship between SLPI levels in AOF and acute histologic chorioamnionitis (HC). AOF of the baby was obtained during delivery from 24(0/7) to 36(6/7) weeks of gestational age (preterm group, n=94) and from 37(0/7) to 41(6/7) weeks of gestational age (term group, n=27) just after birth. SLPI expression levels among five classifications were compared to the intensity of acute HC as follows: no inflammation, acute subchorionitis, acute chorionitis, acute chorioamnionitis, and funisits. The SLPI and matrix metalloproteinase-8 (MMP-8) concentrations of AOF were determined using Enzyme Linked Immunosorbent Assay. Histologic examination of the placenta and membranes was performed after delivery. SLPI concentrations in AOF inversely decreased according to the intensity of acute HC (161.62ng/mL in funisitis, 134.83ng/mL in acute chorioamnionitis, 749.35ng/mL in acute chorionitis, 953.05ng/mL in acute subchorionitis, and 1126.77ng/mL in no inflammation [p=.021]). The MMP-8 concentrations in AOF and maternal serum C-reactive protein were the highest in funisitis. The SLPI/ MMP-8 ratio was low in subgroup with acute chorioamnionitis and funisitis. Along with increased MMP-8 levels, decreased SLPI levels in AOF of the baby could be an additional factor in predicting acute HC immediately after birth.

Possibilities of predicting lesions of the hepatobiliary system in children with community-acquired pneumonia

Annotation. The prognostic criteria of complications of community-acquired pneumonia and the possibility of developing disorders of the hepatobiliary system (HBS) depending on the concentration in the serum of the secretory leukocyte protease inhibitor (SLPI) were studied. The data of clinical and laboratory examination of 338 children with community-acquired pneumonia aged from one to three years were analyzed. Statistical processing of the results was performed using the system “IBM SPSS Statistica” 12 using parametric and non-parametric methods. It was found that in young children with pneumonia in the serum increases the concentration of SLPI, the level of which depends on the course and severity of pneumonia. It has been shown that the development of lobar pneumonia is significantly higher in patients from the SLPI cohort IV quartile (OR – 1.986, 95% CI – 1.864-2.356), compared with children from the cohort SLPI II and III quartile (OR – 0.476, 95% CI – 0.405- 0.559, OR – 0.494, 95% CI – 10.423-0.576, respectively). At the same time, at the values of SLPI at the level of III-IV quartile (OR – 1.923, 95% CI – 1.457-1.866) there is the development of community-acquired pneumonia. It was found that the development of pathological processes in the organs of HBS is associated with increased levels of SLPI. Thus, patients with polysegmental pneumonia and SLPI III/IV quartile (OR – 2.190, 95% CI – 1.810-2,754) are twice as likely to develop pathology of the hepatobiliary system than children with SLPI I/II quartile (OR – 1.153, 95% CI – 1.071-1.527). The established fact indicates the involvement of SLPI in the pathogenesis not only of pneumonia, but also in disorders of HBS.

Oral secretory leukocyte protease inhibitor (SLPI): Associations with oropharyngeal cancer and treatment outcome.

BackgroundRates of oropharyngeal cancer (OPC) associated with alcohol & tobacco use have decreased, while human papillomavirus (HPV) associated OPC has increased among men in the US. Secretory leukocyte protease inhibitor (SLPI), detectable in a variety of secretions, has been implicated in cancers of the head and neck, associated with tumor progression and anti-viral activity. Using the recently verified oral gargle specimen, this study aimed to assess the association of salivary SLPI expression with risk of OPC and response to treatment.MethodsA case-control study design compared levels of salivary SLPI among OPC cases to age and tobacco smoking matched healthy controls. Oral HPV DNA and SLPI was quantified from oral gargle specimens. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations of oral SLPI and risk of OPC and treatment outcomes.ResultsIn crude and adjusted analyses of 96 OPC cases and 97 age- and smoking-matched controls, OPC was not significantly associated with oral gargle SLPI levels. Among cases, oral SLPI was associated with tonsillectomy (p = 0.018) and among controls oral SLPI was associated with HPV in the oral gargle (p = 0.008). Higher concentrations of SLPI was significantly associated with increased odds of incomplete treatment response (T2: OR: 12.39; 95% CI: 1.44–106.72; T3: OR: 9.86; 95% CI: 1.13–85.90) among all cases, but not among P16+ cases.ConclusionsSalivary SLPI was not associated with OPC risk but was associated with higher odds of an incomplete treatment response.

Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24–26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R2 = 0.75) and interleukin-8 (R2 = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.

Plasma concentrations of secretory leukocyte protease inhibitor (SLPI) differ depending on etiology and severity in community-onset bloodstream infection

The severity of bloodstream infections (BSI) depends on pathogen, source, and host factors. Secretory leukocyte protease inhibitor (SLPI) counteracts tissue damage, balances inflammation, and is increased in pneumonia and sepsis. We aimed to evaluate whether SLPI production differs depending on etiology, disease severity, and sex in BSI and to correlate SLPI with markers of inflammation and immunosuppression. Of the adult patients with BSI, 109 were included and sampled repeatedly, from hospital admission through day 28. Controls (blood donors) were sampled twice. SLPI in plasma was measured with enzyme-linked immunosorbent assay (ELISA) technique. Streptococcus pneumoniae and Staphylococcus aureus etiology were associated with higher SLPI than Escherichia coli on days 1–2 and 3. On day 1–2, subjects with sepsis had higher SLPI concentrations than those with non-septic BSI. Pneumonia was associated with higher SLPI than a non-pulmonary source of infection. SLPI co-varied with inflammatory markers. SLPI concentrations did not differ with regard to sex in the full cohort, but men with pneumonia had higher SLPI than women on day 1–2. S. pneumoniae and S. aureus BSI were associated with higher SLPI, when compared to E. coli. Severity and pneumonia, as well as male sex in the pneumonia sub-cohort, were factors independently associated with higher SLPI.

Elevated Concentrations of SERPINE2/Protease Nexin-1 and Secretory Leukocyte Protease Inhibitor in the Serum of Patients with Papillary Thyroid Cancer

Introduction. SERPINE2 and secretory leukocyte protease inhibitor (SLPI) are proteins with anticoagulant properties which could promote solid tumor growth. However, their role in the pathogenesis of thyroid cancer has not been determined. Materials and Methods. The aim of this study was to assess serum SERPINE2 and SLPI concentrations in a group of 36 patients with papillary thyroid cancer (PTC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum SERPINE2 and SLPI concentrations were measured using specific ELISA methods. Results. Significantly higher concentrations of SERPINE2 and SLPI were found in patients with PTC as compared with MNG and controls. Positive correlation was found between SERPINE2 and SLPI concentrations in PTC patients. The levels of SERPINE2 and SLPI did not differ significantly between MNG and healthy controls. Conclusions. Our results indicate that SERPINE2 and SLPI play a significant role in the development of papillary thyroid cancer and imply that the evaluation of serum concentrations of both anticoagulant molecules may be considered as additional marker for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors.

Distribution and factors associated with salivary secretory leukocyte protease inhibitor concentrations.

This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men. Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively. Among men aged 18-73years, the median SLPI concentration was 492.0ngml-1 (range: 2.3-1919.9). In multivariable modeling, men in Brazil and younger men (18-30years) were more likely to have higher levels of SLPI [adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively]. Men with a self-reported sexually transmitted diseases diagnosis in the past 6months were more likely to have higher SLPI levels (aOR 2.98; 95% CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI (aOR 0.34; 95% CI: 0.15-0.79). Similar results were observed for linear regression models. Secretory leukocyte protease inhibitor concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation.

Elevated concentration of secretory leukocyte protease inhibitor in the cervical mucus before delivery

Cervical remodeling during parturition progresses under exquisite regulation by immunologic mediators and proteases. Secretory leukocyte protease inhibitor is a secretory protein that can function as an antimicrobial peptide, an antiinflammatory molecule, and aprotease inhibitor. The involvement of secretory leukocyte protease inhibitor in cervical remodeling before and during parturition is understood poorly. We aimed to reveal the role of secretory leukocyte protease inhibitor in the cervical remodeling process before normal term delivery and to evaluate its utility as a predictive biomarker for timing of delivery. Cervical mucus samples were collected prospectively at weekly prenatal visits from a cohort of pregnant women at term. Thesecretory leukocyte protease inhibitor concentrations in 95 mucus samples that were obtained from 49 women with uncomplicated pregnancy who subsequently underwent normal vaginal delivery were assessed. Alterations in secretory leukocyte protease inhibitor concentrations at term and the association of secretory leukocyte protease inhibitor levels with the time to delivery were analyzed. A moderate positive correlation with significance was detected between cervical mucus secretory leukocyte protease inhibitor concentrations and days to delivery (r= 0.38; P= .0001). The secretory leukocyte protease inhibitor concentration was significantly higher in samples that were collected within 7 days of delivery when compared with samples that were collected >7 days before delivery (P= .001). Secretory leukocyte protease inhibitor concentrations were also significantly higher in samples from women with premature rupture of membranes when compared with those without premature rupture of membranes (P= .01), all of whom delivered within 7 days. A logistic regression analysis revealed that the cervical secretory leukocyte protease inhibitor level was a significant parameter for the prediction of the onset of delivery. (P= .017; unit odds ratio, 1.28; 95% confidence interval, 1.07-1.61). A cut-off value of cervical secretory leukocyte protease inhibitor/total protein topredict delivery within 7 days was determined to be 1.62 μg/mg (sensitivity, 0.69; specificity, 0.72) using receiver operating characteristic curve-analysis. Secretory leukocyte protease inhibitor concentrations in the cervical mucus elevate progressively before delivery in uncomplicated term pregnancies. Our findings suggest that cervical secretory leukocyte protease inhibitor is a candidate biomarker for delivery prediction.

Human Epididymis Protein 4 and Secretory Leukocyte Protease Inhibitor in Vaginal Fluid: Relation to Vaginal Components and Bacterial Composition

Human epididymis protein 4 (HE4) is a protease inhibitor and a recently identified serum biomarker for ovarian cancer. Properties of HE4 in the genital tract of healthy women have not been evaluated. We evaluated associations between HE4 and a second vaginal protease inhibitor, secretory leukocyte protease inhibitor (SLPI), with vaginal concentrations of innate immune mediators or proteases and with the types of vaginal bacterial communities. Vaginal secretions were collected from 18 healthy reproductive age women and assayed by enzyme-linked immunosorbent assay for concentrations of HE4, SLPI, kallikrein 5, cathepsin B, interleukin 1β (IL-1), IL-1 receptor antagonist (IL-1 ra), mannose-binding lectin (MBL), the inducible 70-kDa heat shock protein, and matrix metalloproteinase (MMP)-8. The species composition of vaginal bacterial communities in 16 women was characterized by sequencing amplicons derived from 16S bacterial ribosomal RNA genes. Correlations between any 2 assays were analyzed by the Spearman rank correlation tests. Differences in the concentrations of HE4 and SLPI, and between soluble components and vaginal community types, were analyzed by the Mann-Whitney U tests. Vaginal HE4 concentrations, but not SLPI levels, were positively correlated with levels of IL-1β (P = .0152), IL-1ra (P = .0061), MBL (P = .0100), and MMP-8 (P = .0315). The median vaginal HE4 level, as well as concentrations of MBL, IL-1β, IL-1ra, and MMP-8, was highest when Gardnerella vaginalis dominated a vaginal community. The association between HE4, elevated levels of proteases, immune mediators and high proportions of G vaginalis strongly suggests that HE4 is a component of the proinflammatory immune response in the female genital tract.

Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure

Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.

Antimicrobial peptide plasma concentrations in patients with community-acquired pneumonia

Community-acquired pneumonia (CAP) is a common and potentially life-threatening infection. Innate immunity is the first line of defence, and antimicrobial peptides (AMPs) produced by white blood cells and at epithelial barriers participate by killing microorganisms and neutralizing bacterial toxins. We wanted to investigate whether concentrations of AMPs (1) are increased in CAP, (2) predict the clinical outcome, and (3) differ depending on the causative microbe. Plasma concentrations of AMPs were measured using an enzyme-linked immunosorbent assay in 89 patients with CAP, 21 patients with non-respiratory tract infections (non-RTI), and 63 healthy control subjects. In subjects with CAP, mean plasma concentrations of secretory leukocyte protease inhibitor (SLPI) and bactericidal/ permeability-increasing protein (BPI) were significantly higher than in healthy control subjects (85 vs 45 ng/ml, p < 0.001 and 48 vs 10 ng/ml, p < 0.001, respectively), but less markedly increased in patients with non-RTI (68 ng/ml, p = 0.06 and 41 ng/ml, p = 0.43). LL-37 and human neutrophil peptides 1-3 (HNP 1-3) levels were not increased in subjects with CAP. Levels of BPI and SLPI did not correlate to severity of disease, and AMP levels did not differ depending on the causative agent. Interestingly, male subjects with CAP displayed increased concentrations of SLPI compared to females. This was not observed in subjects with non-RTI and healthy control subjects. Subjects with CAP showed increased plasma concentrations of SLPI and BPI compared to healthy control subjects. The finding of higher SLPI levels in male subjects with CAP implies that there are sex-dependent immunological differences in SLPI turnover.

The negative feedback mechanism between SLPI and IFNγ is impaired in tuberculosis patients (164.7)

Abstract Mycobacterium tuberculosis increases IFNγ secretion which plays an important role in granuloma formation and clearance of it. Also, the exposure of macrophages to M. tuberculosis increases secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor with antimycobacterial activity. Therefore, the aim of the present study was to determine the role of a putative interaction between IFNγ and SLPI in PBMC derived from healthy donors (HD) and tuberculosis patients (TB). Peripheral blood mononuclear cells (PBMC) from TB and HD were treated with Mtb antigen and IFNγ and SLPI was determined by ELISA. Our results showed that the stimulation with Mtb of PBMC from HD, it decreased SLPI (p&amp;lt;0.01) while increased IFNγ secretion. Furthermore, the blockage of IFNγ reversed the effect of the Mtb antigen on SLPI secretion in PBMC-derived HD. Surprisingly Mtb antigen did not modify the SLPI secretion in PBMC-derived from TB, although it increased IFNγ. Furthermore, the mAb against IFNγ did not affect the SLPI secretion. When plasma levels of SLPI and IFNγ were measured, we found a positive correlation between them in TB but not in HD. Moreover, tuberculosis patients showed more SLPI in plasma, being the levels higher with the severity of the disease. Overall, these results suggest that there is a negative cross talk between IFNγ and SLPI in HD that it is not present in TB patients. Therefore, the higher concentration of IFNγ and SLPI might contribute to control the infection.

Periodontal pathogens affect the level of protease inhibitors in gingival crevicular fluid

In periodontitis, an effective host-response is primarily related to neutrophils loaded with serine proteases, including elastase (NE) and protease 3 (PR3), the extracellular activity of which is tightly controlled by endogenous inhibitors. In vitro these inhibitors are degraded by gingipains, cysteine proteases produced by Porphyromonas gingivalis. The purpose of this study was to determine the level of selected protease inhibitors in gingival crevicular fluid (GCF) in relation to periodontal infection. The GCF collected from 31 subjects (nine healthy controls, seven with gingivitis, five with aggressive periodontitis and 10 with chronic periodontitis) was analyzed for the levels of elafin and secretory leukocyte protease inhibitor (SLPI), two main tissue-derived inhibitors of neutrophil serine proteases. In parallel, activity of NE, PR3 and arginine-specific gingipains (Rgps) in GCF was measured. Finally loads of P. gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola were determined. The highest values of elafin were found in aggressive periodontitis and the lowest in controls. The quantity of elafin correlated positively with the load of P. gingivalis, Ta. forsythia and Tr. denticola, as well as with Rgps activity. In addition, NE activity was positively associated with the counts of those bacterial species, but not with the amount of elafin. In contrast, the highest concentrations of SLPI were found in periodontally healthy subjects whereas amounts of this inhibitor were significantly decreased in patients infected with P. gingivalis. Periodontopathogenic bacteria stimulate the release of NE and PR3, which activities escape the control through degradation of locally produced inhibitors (SLPI and elafin) by host-derived and bacteria-derived proteases.

Protease inhibitor levels in periodontal health and disease

Our previous study showed that protease inhibitors were attenuated by the periodontal pathogen Porphyromonas gingivalis in cultured gingival epithelial cells. We hypothesize that fewer protease inhibitors would be present in more advanced periodontal disease sites, where the level of P. gingivalis may be high. The goal of this study was to investigate the relationship between the protease inhibitor [secretory leukocyte protease inhibitor (SLPI), elastase-specific inhibitor (ELAFIN) and squamous cell carcinoma antigen (SCCA)] levels in gingival crevicular fluid and the number of P. gingivalis micro-organisms in subgingival plaque. Plaque samples from subjects without (n = 18) and with moderate to advanced periodontitis (n = 41) were used to quantify P. gingivalis using real-time PCR. Protease inhibitor levels in the gingival crevicular fluid of all the subjects were determined by ELISA. P. gingivalis was detected in 68.3% of patients with periodontitis, while 16.7% of subjects without periodontitis had a detectable level of P. gingivalis. Patients with periodontitis and P. gingivalis in their plaque exhibited lower SLPI and ELAFIN levels (p < 0.001) compared with control subjects without periodontitis. Secretory leukocyte protease inhibitor was also reduced (p < 0.05) in gingival crevicular fluid of periodontitis patients without a detectable level of P. gingivalis. Periodontitis patients with high vs. low levels of P. gingivalis exhibited reciprocal mean levels of SLPI and ELAFIN concentrations. The reduced concentrations of SLPI and ELAFIN may contribute to the loss of host protective capacity and increase susceptibility to breakdown from chronic infection. The work of this investigation may aid in finding diagnostic and prognostic markers in periodontal health and disease and may also help in finding pharmacological targets directed against periodontal inflammation.

Secretory leukocyte protease inhibitor inhibits neutrophil apoptosis

The secretory leukocyte protease inhibitor (SLPI) is a major anti-elastase barrier at the epithelial surfaces of upper respiratory tract. In addition to its anti-protease activity, SLPI has been shown to express anti-bacterial, anti-viral and anti-inflammatory properties. We measured SLPI concentration in nasal lavage fluid of healthy volunteers after challenge with endotoxin (LPS) and evaluated SLPI effects in vitro on neutrophil chemotaxis, adhesion, cytokine (IL-8) release and apoptosis. SLPI concentration in nasal lavage (n = 9) 2, 6 and 24 h after the challenge with LPS (25 µg) increased from 32% to 238% compared with baseline (226 ± 71 ng/mL). In vitro, SLPI (20-80 µg/mL) induced neutrophil chemotaxis (sixfold, P < 0.001) and decreased neutrophil apoptosis by 73% (P = 0.006), relative to controls. However, SLPI had no affect on IL-8 release or neutrophil adhesion to fibronectin. SLPI-positive immunoreactivity was co-localized with neutrophils in lung specimens from patients with COPD. Our findings indicate upregulation of SLPI in response to LPS in nasal secretions and show anti-apoptotic effects of SLPI in primary human neutrophils suggesting a new role of SLPI during neutrophilic inflammation.

Abstract 828: Progranulin is a good predictive biomarker in ovarian cancer patients followed in first remission

Abstract Both secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are upregulated and overexpressed in ovarian cancers (OvCa). SLPI has important function in carcinogenesis as a proliferation and survival factor. PGRN is a potent growth and survival factor for cancer cells, and binds to SLPI, the complex of which protects PGRN from degradation by elastase. Recently, human epididymis protein 4 (HE4), located at the same whey acidic protein (WAP) genomic locus as SLPI and with similar structure, has been FDA approved for monitoring OvCa recurrence. We explored the application of SLPI and PGRN as monitoring biomarkers for OvCa recurrence. Archived plasma samples from 23 OvCa patients in first clinical remission, that had been collected prospectively every 3 months until relapse, were used to measure SLPI and PGRN concentrations; archival CA125 results and HE4 measured using commercially available ELISA were controls. Initial PGRN concentration, at study entry, was identified as a predictive factor. Thirteen of 23 patients had elevated PGRN concentrations and normal CA125 at the time of clinical remission. Eleven of those 13 patients recurred within 18 months (p= &amp;lt;0.03), with sensitivity and specificity of 79% and 78%, respectively. HE4 progressively increased in 19 of 23 patients, and 9 patients had positive change &amp;gt;12 months prior to the clinical progression. Only one patient maintained stable HE4 concentration and remains in remission; 3 patients who had stable HE4 concentrations relapsed at 14, 18, and 30 months. Five patients are still in clinical remission, but HE4 concentrations are increased in 4 of 5. In our small panel, HE4 had sensitivity and specificity of 77% and 10%, respectively. For the first time, our work evaluated SLPI and PGRN as predictive and monitoring biomarkers for OvCa recurrence. Additional study is needed to validate the usefulness of PGRN as a predictive factor in OvCa remission. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 828.

Effects of Pregnancy and Bacterial Vaginosis on Proinflammatory Cytokine and Secretory Leukocyte Protease Inhibitor Concentrations in Vaginal Secretions

We compared vaginal proinflammatory cytokine and secretory leukocyte protease inhibitor (SLPI) concentrations among pregnant and nonpregnant women according to bacterial vaginosis (BV) status. One-hundred and twenty-two women at 12–20 weeks' gestation and 133 nonpregnant controls had vaginal concentrations of interleukin (IL)-1β, IL-6, IL-8, and SLPI measured by enzyme immunoassay. Multivariable linear regression was used to evaluate factors independently associated with vaginal cytokine and SLPI response. Pregnancy and BV were both independently associated with increased vaginal concentrations of IL-1β and IL-8; pregnant women had increased concentrations of SLPI, while women with BV had decreased SLPI concentrations.

Bacterial Vaginosis, Not HIV, Is Primarily Responsible for Increased Vaginal Concentrations of Proinflammatory Cytokines

The relative effect of HIV-1 infection compared with vaginal infections on vaginal cytokine concentrations is not well characterized. We compared vaginal fluid samples from HIV-1-infected women with those from HIV-negative women, to assess the effect of HIV-1 infection on concentrations of vaginal proinflammatory cytokines and the mucosal defense molecule secretory leukocyte protease inhibitor (SLPI). Twenty-seven HIV-1-infected women and 54 HIV-negative controls, matched for bacterial vaginosis (BV) status, had proinflammatory cytokine [interleukin (IL)-1beta, IL-6, IL-8] and SLPI concentrations measured from archived cervicovaginal lavage and vaginal swab samples using an enzyme-linked immunosorbent assay (ELISA). Log-transformed concentrations were compared by BV and HIV status in univariate analysis using Student's t-test, and in multivariate analysis using a linear regression model. In univariate analysis there were no significant differences in cytokine concentrations among HIV-1-infected and HIV-negative women. In a multivariable linear regression model, BV was significantly associated with an increase in IL-1 beta (p = 0.003). HIV infection was associated with an increased concentration of SLPI (p = 0.008), while BV status was significantly associated with a decrease in SLPI concentrations (p = 0.005). Neither HIV nor BV was associated with changes in IL-6 or IL-8. HIV does not have a major impact on vaginal concentrations of proinflammatory cytokines when controlling for the presence of bacterial vaginosis.

The Effect of Secretory Leukocyte Protease Inhibitor (SLPI) on Ischemia/Reperfusion Injury in Cardiac Transplantation

We investigated the role of secretory leukocyte protease inhibitor (SLPI) in ischemia/reperfusion injury in cardiac transplantation. SLPI-/- mouse hearts and wild-type (WT) controls were transplanted immediately or after 10 h of cold ischemia (CI). Recombinant SLPI (rSLPI) was added to the preservation solution or given systemically. After evaluation of myocardial performance, grafts were investigated for histology, SLPI, TNF-alpha, TGF-beta, NF-kappaB and protease expression at indicated time points. Early myocardial contraction was profoundly impaired in SLPI-/- hearts exposed to CI and associated with high intra-graft protease expression. Systemic administration of rSLPI had no effect, however, when SLPI was added to the preservation solution, myocardial contraction was restored to normal. At 10 days, inflammation, myocyte vacuolization and necrosis were significantly more severe in SLPI-/- hearts. SLPI gene expression was detected in WT mice at 12 and 24 h and was significantly higher after CI. SLPI protein was observed at 24 h and 10 days. High intra-graft concentrations of SLPI after administration of rSLPI were inversely correlated with protease levels early and TGF-beta expression late after reperfusion. SLPI plays a crucial role in early myocardial performance and postischemic inflammation after cardiac transplantation. A dual inhibitory effect on protease and TGF-beta expression might be the underlying mechanism.