Bronchopulmonary dysplasia (BPD) continues to be a major cause of morbidity in premature infants. An imbalance between neutrophil elastase and its inhibitors has been implicated in BPD. Serine protease inhibitor (SERPIN)B1 is an inhibitor of neutrophil proteases, including neutrophil elastase (NE) and cathepsin G (cat G). Recent studies suggest that SERPINB1 could provide protection in the airways by regulating excess protease activity associated with inflammatory lung disorders. In this study, we determined the distribution and ontogeny of SERPINB1 in the baboon lung and characterized the expression of SERPINB1 in baboon models of BPD. SERPINB1 expression was detected in the conducting airway and glandular epithelial cells in addition to neutrophils, macrophages, and mast cells. SERPINB1 mRNA and protein expression increased with advancing gestational age and in the new BPD model. In contrast, SERPINB1 expression levels were decreased in the old BPD model. Furthermore, SERPINB1 was detected as a high-molecular-mass (HMM) complex in lung tissue and bronchoalveolar lavage fluid samples from the BPD group. Analysis of the HMM complex by coimmunoprecipitation showed that these complexes were formed between SERPINB1 and NE or cat G. High-performance liquid chromatography (HPLC) ion trap mass spectrometry verified the presence of SERPINB1 in HMM complexes. Finally, NE activity level was compared between new and old baboon models of BPD and was found to be significantly lower in new BPD. Thus SERPINB1 upregulation in new BPD may be protective by contributing to the regulation of neutrophil proteases NE and cat G.
"We found that Serpin B1 is upregulated by Securinine stimulation. Transcription of Serpin B1 is known to be regulated by NF-kB , , suggesting that the some of the same proteins that regulate inflammation also regulate Serpin B1. Figure 7 shows that Securinine quickly induces phosphorylation of p38, suggesting that Securinine-induced phosphorylation of p38 may initiate the upregulation of Serpin B1. It also seems reasonable that Serpin B1 is acting in a protective capacity, since upregulation of Serpin B1 has a positive effect on bacterial clearance . "
[Show abstract][Hide abstract] ABSTRACT: Securinine, a GABA(A) receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA(A) receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5'-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca(2+) binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.
PLoS ONE 09/2012; 7(9):e41278. DOI:10.1371/journal.pone.0041278 · 3.23 Impact Factor
"SERPINB1 is broadly expressed and is at particularly high levels in the cytoplasm of neutrophils (11, 12). SERPINB1 has been found complexed to neutro phil proteases in lung fluids of cystic fibrosis patients and in a baboon model of bronchopulmonary dysplasia (13, 14). Although these studies suggest a role for SERPINB1 in regulating NSP activity, it is unclear whether these complexes reflect an important physiological role for SERPINB1 in the lung air space. "
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Experimental Medicine 09/2007; 204(8):1901-9. DOI:10.1084/jem.20070494 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neutrophils and complement system are the critical elements of innate immunity mainly due to participation in the first line of defense against microorganisms by means of phagocytosis, lysis of bacteria and activation of naive B-lymphocytes. In this report we provide an overview of the up to date information regarding the neutrophil and complement system's functional ability in newborn infants in association with the maternal conditions that exist during the intrauterine stage, gestational age and post-neonatal pathology. The neonates' capacity to control the neutrophil and complement protein activation process has also been discussed because of the evidence that uncontrolled activation of these immune elements provides a significant contribution to the tissue damage and subsequent pathology. The authors are confident that despite the many unanswered questions this review updates their knowledge and points the need for further research to clarify the role of the age-associated dysfunction of neutrophils and complement system in the infection and inflammation related pathology of newborn infants.
The Indian Journal of Pediatrics 03/2007; 74(2):185-91. DOI:10.1007/s12098-007-0013-2 · 0.87 Impact Factor
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