Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.

Background Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1-conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. Conclusion These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response

Plasma levels of alpha1-antichymotrypsin and secretory leukocyte proteinase inhibitor in healthy and chronic obstructive pulmonary disease (COPD) subjects with and without severe α1-antitrypsin deficiency

BACKGROUND: Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency. METHODS: Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7). Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis. RESULTS: No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively). CONCLUSION: Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

Serine protease inhibitors in the upper and lower airways

Proteases and their inhibitors are implicated in the physiology and pathology of the airways. Protease inhibitors include those produced locally, such as secretory leukocyte protease inhibitor (SLPI), and those produced mainly by the liver that can reach the airways via passive diffusion, such as alpha1-antitrypsin (AAT). SLPI is a significant component of the anti-neutrophil elastase shield in the respiratory tract and is therefore complementary to the AAT, a major inhibitor of neutrophil elastase and protease 3. Inherited, severe AAT deficiency is a recognised genetic risk factor for the development of chronic obstructive lung disease (COPD), whereas no gene polymorphism has been found for SLPI. There is, therefore, no indication of whether a deficit in SLPI could be responsible for the development of COPD in patients that otherwise have sufficient levels of AAT. To test the hypothesis that a compensatory increase in levels of SLPI might favourably improve the protease/protease-inhibitor balance in AAT deficient individuals, we analysed plasma levels of SLPI in healthy subjects with and without severe AAT deficiency. The finding that plasma SLPI did not differ between these groups led to the conclusion that SLPI does not compensate for the deficiency of plasma AAT. SLPI levels in bronchial lavage fluid from asthma and COPD patients are remarkably higher than in plasma, suggesting that plasma may not be the appropriate biological fluid in which to measure SLPI. In addition to anti-protease activities, both SLPI and AAT, exhibit other anti-inflammatory properties in vitro and in vivo. Therefore, an understanding of the mechanisms involved in AAT and SLPI protein expression, release and consumption provides important knowledge on the dynamics of the regulation of the protease/anti-protease and other systems in the inflammatory responses. Our studies revealed that SLPI expression and release by epithelial cells are dependent on the interaction of epithelial and mast cells and that endotoxin (LPS) increases SLPI levels in nasal lavage. Interestingly, while AAT was found to inhibit LPS-induced monocyte and neutrophil responses in vitro, and to suppress nasal interleukin-8 (IL-8) release in LPS-challenged individuals, in vivo, SLPI effects shown to be much more complex. In vitro, SLPI significantly inhibited LPS-stimulated IL-8 release from monocytes but had no effect in neutrophil models. Indeed, SLPI itself stimulated neutrophil, but not monocyte, chemotaxis and adhesion. These findings further expand our knowledge on the regulatory effects of SLPI and AAT during inflammatory reactions which may be potentially more biologically profound than their ability to inhibit proteases

Spontaneous Cerebrospinal Fluid Otorrhea from a Persistent Tympanomeningeal Fissure Presenting as Recurrent Serous Otitis Media

We describe spontaneous cerebrospinal fluid (CSF) otorrhea through a patent tympanomeningeal (Hyrtl) fissure presenting as recurrent serous otitis media. The CSF leak was observed when a drain was placed through the tympanic membrane by an otologist. The diagnosis was then confirmed by computed tomography and magnetic resonance imaging, and the patient underwent a successful surgical treatment via a retrosigmoid approach. We describe the case and review causes of spontaneous CSF rhinorrhea/otorrhea

Human mast cells decrease SLPI levels in type II – like alveolar cell model, <it>in vitro</it>

Abstract Background Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p Conclusion These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response.</p

Serum and bronchial lavage fluid concentrations of IL-8, SLPI, sCD14 and sICAM-1 in patients with COPD and asthma

Background: Airway inflammation is associated with an increased expression and release of inflammatory reactants that regulate processes of cell migration, activation and degranulation. The purpose of this study was to quantify bronchial lavage (BAL) fluid and serum levels of chemokine (IL-8), secretory leukocyte protease inhibitor (SLPI), soluble intracellular adhesion molecules-1 (sICAM-1) and sCD14, as surrogate markers of inflammatory and immune response in asthma and chronic obstructive pulmonary disease (COPD) patients with similar disease duration time. Methods: Biomarkers in serum and BAL fluid from asthma (n = 13) and COPD (n = 25) patients were measured using commercially available ELISA kits. Results: We found that in asthma and COPD groups the concentrations of IL-8 and SLPI are significantly higher in BAL fluid than in serum, while levels of sICAM-1 and sCD14 in BAL fluid are significantly lower than in serum. Of these 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma (P < 0.05). In both groups, BAL IL-8 correlated with SLPI (r = 0.577, P < 0.01 and r = 0.589, P < 0.05, respectively). In patients with COPD the BAL sICAM-1 correlated with sCD14 (r = 0.576, P < 0.01), while in asthma patients BAL sICAM-1 correlated with FEV,/FVC (r= 0.418, P < 0.01). Moreover, in asthma patients the serum SLPI correlated with sCD14 (r=0.688, P < 0.01) and serum sICAM-1 negatively correlated with FEV1/FVC (r= -0.582, P < 0.05). Conclusion: Our findings point to the importance of selecting a correct biological fluid when analyzing specific biomarkers, and also show that of 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma. 2007 Published by Elsevier Ltd

BMC Pulmonary Medicine Plasma levels of alpha1-antichymotrypsin and secretory leukocyte proteinase inhibitor in healthy and chronic obstructive pulmonary disease (COPD) subjects with and without severe α1-antitrypsin deficiency

Abstract Background: Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency