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Enzyme-Releasing Peptide
Published in Jason Kelley, Cytokines of the Lung, 2022
Allen B. Cohen, Edmund J. Miller, Cassandra MacArthur
Investigators have also studied neutrophil elastase in relation to emphysema. Numerous studies have examined the proteinase-inhibitor balance in the lungs, but few of these did careful quantification of neutrophil enzymes immunologically. Both normal subjects and smokers have neutrophil elastase in their bronchoalveolar lavage fluids (Jochum et al., 1985; Gast et al., 1990). Gast and colleagues (1990) found that the concentration of leukocyte elastase-alpha1-proteinase inhibitor complexes was 11-fold higher in patients with emphysema than in normal subjects and that these complexes were negatively correlated with lung function. Fera and colleagues (1986) demonstrated that smoking increased neutrophil elastase in bronchoalveolar lavage fluids. In recent studies (Cohen et al., 1990, Cohen et al., 1991a), we tried to reduce the level of neutrophil elastase in bronchoalveolar lavage fluids of patients with emphysema by treating them with the microtubule-disrupting drug, colchicine, which reduces neutrophil enzyme secretion (Zurier et al., 1974). We also carried out studies to determine which drugs were most effective at suppressing enzyme release when the neutrophils were stimulated with macrophage-conditioned medium and other stimulants (Stevens et al., 1989). We determined that colchicine could not reduce the concentration of neutrophil elastase in current smokers with emphysema, but it could reduce this concentration by more than 50% in exsmokers with emphysema (Cohen et al., 1990a).
Pathophysiological Responses to Endotoxin in Humans
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony F. Suffredini, Naomi P. O’Grady
Ibuprofen is a cyclooxygenase inhibitor that alters many of the associated LPS responses. When given prior to endotoxin administration, ibuprofen significantly decreased the magnitude of symptoms, fever, respiratory frequency, and resting energy expenditure but did not change the cardiovascular response (heart rate, mean arterial pressure, cardiac output, left ventricular ejection fraction) (51,94). Leukocyte responses were not altered but neutrophil elastase release was enhanced (95). Stress hormone responses were diminished (51). Cyclooxygenase products are important inhibitors of cytokine production, and blocking prostaglandin production in subjects given endotoxin was associated with enhanced levels of TNF and IL-6 (42,44,95). However, the enhanced blood cytokine levels were not associated with any symptoms or increased alterations in cardiovascular responses (94). These data demonstrate that the cardiovascular response is not dependent on fever and that prostaglandins have important effects on cytokine responses in vivo.
Correction of the Genetic Defect in Alpha-1 Antitrypsin Deficiency by Somatic Gene Therapy
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Randy C. Eisensmith, Savio L. C. Woo
Human α1-antitiypsin (hAAT) is a major serine protease inhibitor. This serum protein is synthesized as a single 394-amino acid polypeptide with a molecular weight of approximately 52,000 daltons (1-3), has a carbohydrate content of about 12%, and contains 6 to 8 sialic acid residues (4,5). Although synthesized and secreted primarily from the liver (6), limited amounts of hAAT are also produced in macrophages (7,8) and monocytes (8,9) as well as parenchymal cells of the lung (10), kidney, and intestine (11,12). hAAT inhibits a variety of serine proteases such as trypsin, chymotiypsin, elastase, renin, urokinase, collagenase, and proteolytic enzymes released from leukocytes and bacteria (13). However, its most important action is as an inhibitor of neutrophil elastase (5,14). The clinical importance of hAAT was recognized following the observation that individuals with markedly deficient hAAT levels in serum develop chronic obstructive pulmonary emphysema (15) and/or infantile liver cirrhosis (16).
Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress
Published in OncoImmunology, 2022
J. Cedervall, M. Herre, A. Dragomir, F. Rabelo-Melo, A. Svensson, C. Thålin, A. Rosell, V. Hjalmar, H. Wallén, H. Lindman, G. Pejler, E. Hagström, M. Hultström, A. Larsson, AK. Olsson
Plasma was collected by terminal heart puncture from mice anaesthetized by intraperitoneal injection of 2% avertin, using citrate (0.011 M) as an anti-coagulant. Citrated venous plasma samples from cancer patients and healthy individuals were collected at Danderyd hospital. ELISA plates (F96 Maxisorp Nunc-immuno plate; Thermo Fisher) were coated with the H3Cit antibody (ab5103; abcam) diluted 1:200 for mouse and 1:500 for human samples or the MPO antibody (HM2164-clone 266–6K1; Hycult Biotechnology) (only human samples) diluted 1:20 and incubated overnight at 4°C. Wells were washed with PBS and blocked with 3% BSA for 1 hour at room temperature. After a washing step, 20 µl undiluted mouse or human plasma were added together with 80 µl or 30 µl dsDNA-peroxidase (POD) antibody (Cell Death ELISAPLUS; Roche) for the H3Cit and MPO ELISA, respectively, and incubated for 2 hours at room temperature. The DNA-POD antibody was diluted 1:20 for mouse, 1:100 for human H3Cit and 1:40 for human MPO detection. Following a washing step, TMB (T8665; Sigma) was added and the absorbance was measured at 650 nm with a microplate reader. Neutrophil Elastase was analyzed using a Human PMN Elastase ELISA kit (ab119553; Abcam), following instructions from the manufacturer.
Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches
Published in Expert Review of Respiratory Medicine, 2022
Auyon J. Ghosh, Brian D. Hobbs
The mechanism of AATD-associated lung disease has historically been attributed to the insufficient inhibition of neutrophil elastase due to AAT levels below the putative protective threshold. The threshold was approximated from a series of population-based studies in the 1970s and 1980s, though the derivation of the exact threshold of 11 μm (0.57 g/L) does not appear to exist in the literature [61,62]. Eventually, the threshold was defined as the 10th percentile of AAT levels in SZ genotype individuals, who were chosen due to the increased risk of lung disease compared to SS genotype individuals [63]. A more recent study by Franciosi and colleagues, however, suggests that this threshold is closer to the 40th percentile in SZ genotype individuals. Furthermore, this study did not find SZ genotype individuals who were never smokers at higher risk of disease regardless of AAT level [64].
Cyclic manner of neutropenia in a patient with HAX-1 mutation
Published in Pediatric Hematology and Oncology, 2018
Funda Erol Cipe, Mehmet Halil Celiksoy, Biray Erturk, Çiğdem Aydogmus
Cyclic neutropenia is a type of congenital neutropenia in which the blood neutrophil count undergoes regular decreases from normal to very low at 18–21-day intervals [5]. Cyclic neutropenia was first described in 1947 [6], and the causative mutation in ELA2 was identified in 1999 [7]. Cyclic neutropenia causes recurrent and sometimes life-threatening infections [5]; e.g., periodontitis, aphthous stomatitis, and typhlitis. The neutrophil count can decrease to below 500/μL; numbers of monocytes, platelets, lymphocytes, and reticulocytes cycle at the same frequency [8]. Cyclic neutropenia patients show accelerated apoptosis of bone marrow progenitor cells at all stages in the cyclic neutropenia cycle. G-CSF therapy increases the survival of bone marrow progenitor cells and the neutrophil count [7]. Cyclic neutropenia is associated with mutations in the ELANE, AP3B1, and Hermansky–Pudlak syndrome type 2 genes [8, 9]. ELANE mutations are the most common causes of severe congenital neutropenia as well as sporadic and autosomal-dominant cyclic neutropenia [9]. Neutrophil elastase produced by neutrophils inhibits production of further neutrophils [5]. Our patient did not have an ELANE mutation.