Levels Of Human Neutrophil Peptides Research Articles

Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population

Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected. The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.

THIS MONTH IN Anesthesiology

The correlation between preoperative responses to experimental pain and clinical postoperative pain is investigated. See the accompanying Editorial View on page 1311 Adaptive support ventilation prevents diaphragmatic atrophy and maintains diaphragmatic contractile activity.Anesthesia and the patient with Restless Legs Syndrome are reviewed.Threshold volume and concentration of ropivacaine for interscalene block are investigated.Cellular effects of clinical usage of helium are reviewed.Although multiple perioperative guidelines acknowledge the prognostic value of symptomatic heart failure symptoms on postoperative outcome, the role of asymptomatic LV dysfunction remains unknown. This study used routine echocardiography in patients undergoing open or endovascular surgery to assess these potential prognostic values. Half of all patients had LV dysfunction, of which 80% were asymptomatic. In patients undergoing endovascular surgery (n = 356), only symptomatic heart failure was associated with 30-day cardiovascular events and long-term cardiovascular mortality. However, associations were seen with both asymptomatic systolic and isolated diastolic LV dysfunction in patients undergoing open vascular surgery (n = 649). This study demonstrated that asymptomatic LV dysfunction is predictive for 30-day and long-term cardiovascular outcome in open vascular surgery patients. Preoperative risk stratification should include heart failure symptoms and routine preoperative echocardiography should be considered for risk stratification in open vascular surgery patients. See the accompanying Editorial View on page 1303 Immune response and genetic predisposition play a role in the pathogenesis of sepsis. Specifically, human neutrophil peptides 1–3, endogenous cationic antimicrobial peptides, have been implicated in host defense against microbes. The genes encoding these human peptides (DEFA1/DEFA3 ) exhibit copy number variations. To evaluate the role of copy number variation on infection complication susceptibility, a case–control study was first performed in 179 patients with severe sepsis and 233 healthy blood donors, and then replicated in an independent cohort of 112 cases and 118 controls. Compared with controls, patients with sepsis were more likely to have high copy number (more than 8) of DEFA1/DEFA3 ; this held true after adjustment for age and gender. Results were replicated in a second age- and gender-matched case–control cohort. Furthermore, patients with large copy number had significantly lower plasma levels of human neutrophil peptides 1–3, tumor necrosis factor-α, interleukin-6, and interleukin-10 compared with patients with low copy number. A higher copy number of DEFA1/DEFA3 (more than 8 copies) was significantly associated with risk of severe sepsis. See the accompanying Editorial View on page 1307 Recently, irritant anesthetics were shown to activate peripheral nociceptors, which may contribute to their hyperalgesic actions and adverse effects in the airways. To test if this occurs via activation of the excitatory ion channel TRPA1, this study used models of isolated guinea pig bronchi to measure bronchoconstriction during exposure to anesthetics. TRPA1 was activated by exposure to isoflurane and desflurane, but not by the nonirritant volatile anesthetics sevoflurane and halothane. In contrast to nonirritants, isoflurane induced TRPA1-dependent constriction of isolated guinea pig bronchi in mice by a TRPA1-dependent mechanism. In addition to their beneficial effects, general anesthetics also produce excitatory effects such as airway irritation and bronchoconstriction. This study demonstrates that activation of TRPA1 may contribute to these adverse effects. See the accompanying Editorial View on page 1309

Tumor necrosis factor and norepinephrine lower the levels of human neutrophil peptides 1-3 secretion by mixed synovial tissue cultures in osteoarthritis and rheumatoid arthritis

IntroductionNeutrophils and monocytes play an important role in overt inflammation in chronic inflammatory joint diseases such as rheumatoid arthritis (RA). The sympathetic nervous system (SNS) inhibits many neutrophil/monocyte functions and macrophage tumor necrosis factor (TNF), but because of the loss of sympathetic nerve fibers in inflamed tissue, sympathetic control is attenuated. In this study, we focused on noradrenergic and TNF regulation of human neutrophil peptides 1-3 (HNP1-3), which are proinflammatory bactericidal α-defensins.MethodsSynovial tissue and cells were obtained from patients with RA and osteoarthritis (OA). By using immunohistochemistry and immunofluorescence, HNP1-3 were tracked in the tissue. With synovial cell-culture experiments and ELISA, effects of norepinephrine, TNF, and cortisol on HNP1-3 were detected.ResultsHNP1-3 were abundantly expressed in the synovial lining and adjacent sublining area but not in deeper layers of synovial tissue. The human β-defensin-2, used as control, was hardly detectable in the tissue and in supernatants. HNP1-3 double-stained with neutrophils but not with macrophages, fibroblasts, T/B lymphocytes, and mast cells. Norepinephrine dose-dependently decreased HNP1-3 levels from RA and OA cells. TNF also inhibited HNP1-3 levels from OA but not from RA cells. Cortisol inhibited HNP1-3 levels only in OA patients. A combination of norepinephrine and cortisol did not show additive or synergistic effects.ConclusionsThis study demonstrated an inhibitory effect of norepinephrine on HNP1-3 of mixed synovial cells. In light of these findings, the loss of sympathetic nerve fibers with low resting norepinephrine levels might also augment the inflammatory process through HNP1-3.

Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases

The traditional view of atherosclerosis has recently been expanded from a predominantly lipid retentive disease to a coupling of inflammatory mechanisms and dyslipidemia. Studies have suggested a novel role for polymorphonuclear neutrophil (PMN)-dominant inflammation in the development of atherosclerosis. Human neutrophil peptides (HNPs), also known as alpha-defensins, are secreted and released from PMN granules upon activation and are conventionally involved in microbial killing. Current evidence suggests an important immunomodulative role for these peptides. HNP levels are markedly increased in inflammatory diseases including sepsis and acute coronary syndromes. They have been found within the intima of human atherosclerotic arteries, and their deposition in the skin correlates with the severity of coronary artery diseases. HNPs form complexes with LDL in solution and increase LDL binding to the endothelial surface. HNPs have also been shown to contribute to endothelial dysfunction, lipid metabolism disorder, and the inhibition of fibrinolysis. Given the emerging relationship between PMN-dominant inflammation and atherosclerosis, HNPs may serve as a link between them and as a biological marker and potential therapeutic target in cardiovascular diseases including coronary artery diseases and acute coronary syndromes.

Human neutrophil peptides 1, 2 and 3 are biochemical markers for metastatic colorectal cancer

Colorectal cancer (CRC) patients have increased levels of human neutrophil peptides 1–3 (HNP1–3) in tumour tissue and plasma. The aim is to study whether the amount of HNP1–3 in tumour and plasma from CRC patients correlate with Dukes’ stages A–D. The amount of HNP1–3 in tumour tissue, normal colonic mucosa, and plasma was determined with mass spectrometry. Plasma levels of HNP1–3 were determined with enzyme-linked immuno-sorbent assay (ELISA). The amount of HNP1–3 determined with mass spectrometry was increased in tumours compared to normal colonic tissue in CRC patients in Dukes’ stage A–D, whereas HNP1–3 in plasma was only elevated in Dukes’ stage D compared to healthy individuals. HNP1–3 plasma concentration determined with ELISA was increased in Dukes’ stages C and D, but not in A and B. It is concluded that HNP1–3 is a potential marker for prognostic assessment, surveillance of patients, and monitoring chemotherapy in CRC patients with advanced disease.