Contrast-induced nephropathy (CIN) is the third leading cause of acute renal failure in hospitalized patients. Endothelial dysfunction, renal medullary ischemia, and tubular toxicity are regarded as the most important factors in the pathogenesis of CIN. Mannose-binding lectin (MBL), a pattern recognition protein of the lectin pathway of complement, has been found to aggravate and mediate tissue damage during experimental renal ischemia/reperfusion (I/R) injury which was alleviated by inhibition with C1 inhibitor, a potent MBL, and lectin pathway inhibitor. In this paper, we highlight the potential role of MBL in the pathogenesis of human CIN. In experimental I/R models, MBL was previously found to induce tubular cell death independent of the complement system. In addition, after binding to vascular endothelial cells, MBL and its associated serine proteases were able to trigger a proinflammatory reaction and contribute to endothelial dysfunction. In humans, urinary MBL was increased after administration of contrast media and in individuals with CIN. Moreover, individuals with normal/high MBL levels were at increased risk to develop radiocontrast-induced renal dysfunction. Hence, MBL and the lectin pathway seem to be a promising target given that a licensed, powerful, human recombinant inhibitor exits to be added to the scarce armamentarium currently available for prophylaxis of CIN.
The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.
Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes.
In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.
The Mannose-binding lectin (MBL) pathway of complement plays a pivotal role in the pathogenesis of ischemia/reperfusion (I/R) injury after experimental ischemic stroke. As comparable data in human ischemic stroke are limited, we investigated in more detail the association of MBL deficiency with infarction volume and functional outcome in a large cohort of patients receiving intravenous thrombolysis or conservative treatment.
In a post hoc analysis of a prospective cohort study, admission MBL concentrations were determined in 353 consecutive patients with an acute ischemic stroke of whom 287 and 66 patients received conservative and thrombolytic treatment, respectively. Stroke severity, infarction volume, and functional outcome were studied in relation to MBL concentrations at presentation to the emergency department. MBL levels on admission were not influenced by the time from symptom onset to presentation (p = 0.53). In the conservative treatment group patients with mild strokes at presentation, small infarction volumes or favorable outcomes after three months demonstrated 1.5 to 2.6-fold lower median MBL levels (p = 0.025, p = 0.0027 and p = 0.046, respectively) compared to patients with more severe strokes. Moreover, MBL deficient patients (<100 ng/ml) were subject to a considerably decreased risk of an unfavorable outcome three months after ischemic stroke (adjusted odds ratio 0.38, p<0.05) and showed smaller lesion volumes (mean size 0.6 vs. 18.4 ml, p = 0.0025). In contrast, no association of MBL concentration with infarction volume or functional outcome was found in the thrombolysis group. However, the small sample size limits the significance of this observation.
MBL deficiency is associated with smaller cerebral infarcts and favorable outcome in patients receiving conservative treatment. Our data suggest an important role of the lectin pathway in the pathophysiology of cerebral I/R injury and might pave the way for new therapeutic interventions.
The complement cascade is a critical mediator of the inflammatory response following cerebral ischemia. Recent work has demonstrated that genetic-deficiency of Mannose-binding lectin(MBL) ameliorates reperfusion injury and improves outcome in the acute phase of stroke. The present study sought to further delineate the pathogenic role of MBL in stroke and to examine whether the neuroprotection associated with MBL-deficiency is sustained beyond the acute phase. We hypothesized that genetic MBL deficiency would suppress complement activation and ameliorate reperfusion injury in the acute phase, but that persistent inhibition of complement into the sub-acute phase would serve to abrogate this neuroprotective effect.
The time-course and localization of post-ischemic cerebral MBL and C3 deposition were characterized using both Western-blot and immunohistochemistry. MBL-a/c null(MBL-KO) mice subjected to transient middle cerebral artery occlusion(MCAO) were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 hours and 7 days.
MBL-a/c rapidly deposit on ischemic endothelium and trigger downstream complement activation in the acute phase. Genetic deficiency of MBL abrogates C3 cleavage as well as the sub-acute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 hours, the neuroprotective effect associated with genetic MBL deletion is not sustained.
Development of a successful anti-complement neuroprotective strategy will require carefully-tailored inhibition coupled with a greater understanding of the functional effects of complement activation during later phases of stroke recovery.
Complement; Stroke; Neuroprotection; Inflammation; Mannose-binding Lectin
After complement system (CS) activation, the sequential production of complement products increases cell injury and death through opsonophagocytosis, cytolysis, adaptive, and inflammatory cell responses. These responses potentiate cerebral ischemia-reperfusion (IR) injury after ischemic stroke and reperfusion. Activation of the CS via mannose binding lectin (MBL)-initiated lectin pathway is known to increase tissue damage in response to IR in muscle, myocardium and intestine tissue. In contrast, the contribution of this pathway to cerebral IR injury, a neutrophil-mediated event, is less clear. Therefore, we investigated the potential protective role of MBL deficiency in neutrophil-mediated cerebral injury after IR. Using an intraluminal filament method, neutrophil activation and cerebral injury were compared between MBL-deficient and wild type C57Bl/6 mice subjected to 60 minutes of MCA ischemia and reperfusion. Systemic neutrophil activation was not decreased in MBL-deficient animals after IR. In MBL-deficient animals, cerebral injury was significantly decreased only in the striatum (p < 0.05). Despite MBL deficiency, C3 depositions were evident in the injured hemisphere during reperfusion. These results indicate that while MBL deficiency results in a modest protection of a sub-cortical brain region during IR, redundant complement pathway activation may overwhelm further beneficial effects of MBL deficiency during reperfusion.
Complement; ischemia; mannose binding lectin; neutrophil; reperfusion; stroke
Mannose-binding lectin (MBL), a pattern recognition innate immune molecule, inhibits influenza A virus infection in vitro. MBL deficiency due to gene polymorphism in humans has been associated with infection susceptibility. These clinical observations were confirmed by animal model studies, in which mice genetically lacking MBL were susceptible to certain pathogens, including herpes simplex virus 2.
We demonstrate that MBL is present in the lung of naïve healthy wild type (WT) mice and that MBL null mice are more susceptible to IAV infection. Administration of recombinant human MBL (rhMBL) reverses the infection phenotype, confirming that the infection susceptibility is MBL-mediated. The anti-viral mechanisms of MBL include activation of the lectin complement pathway and coagulation, requiring serum factors. White blood cells (WBCs) in the lung increase in WT mice compared with MBL null mice on day 1 post-infection. In contrast, apoptotic macrophages (MΦs) are two-fold higher in the lung of MBL null mice compared with WT mice. Furthermore, MBL deficient macrophages appear to be susceptible to apoptosis in vitro. Lastly, soluble factors, which are associated with lung injury, are increased in the lungs of MBL null mice during IAV infection. These results suggest that MBL plays a key role against IAV infection.
MBL plays a key role in clearing IAV and maintaining lung homeostasis. In addition, our findings also suggest that MBL deficiency maybe a risk factor in IAV infection and MBL may be a useful adjunctive therapy for IAV infection.
The involvement of complement system in brain injury has been scarcely investigated. Here we document the pivotal role of mannose binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury.
Methods and Results
Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessels occlusion). We first observed that MBL is deposited on ischemic vessels up to 48h after injury and that functional MBL/MASP2 complexes are increased. Next we demonstrated that: 1) MBL−/− mice are protected from both transient and permanent ischemic injury; 2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24h after ischemia in mice; 3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18h after ischemia, as assessed following 28d in rats.
Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.
cerebral ischemia; endothelium; inflammation; stroke; complement system
Mannose-binding lectin (MBL) is an important component of innate immunity and activator of the lectin complement pathway. Within the MBL2 gene are seven 5′ “secretor” haplotypes that code for altered serum MBL levels and complement activation. However, recent evidence suggests that 3′ MBL2 haplotypes may also modify MBL function and circulating levels. Because MBL and the lectin complement pathway have been implicated in cardiovascular injury, we investigated whether MBL2 haplotypes are independently associated with an increased risk of postoperative myocardial infarction (PMI) in patients undergoing coronary artery bypass graft surgery.
Methods and Results
Genotyping of 18 polymorphic sites within the MBL2 gene was performed in a prospective, longitudinal multi-institutional study of 978 patients undergoing primary coronary artery bypass graft-only surgery with cardiopulmonary bypass between August 2001 and May 2005. After adjustment for multiple comparisons by permutation testing, multivariate, stepwise logistic regression, including a score test, was performed controlling for patient demographics, preoperative risk factors, medications, and intraoperative variables to determine if MBL2 secretor haplotypes are independent predictors of PMI in whites undergoing primary coronary artery bypass graft surgery. Neither the 5′ nor 3′ MBL2 haplotypes alone were associated with an increased incidence of PMI. However, the incidence of PMI in whites (n=843) expressing the combined MBL2 5′ LYQA secretor haplotype (CGTCGG) and 3′ haplotype (CGGGT) was significantly higher than in whites not expressing the haplotype (38% versus 10%; P<0.007). Moreover, the combined MBL2 LYQA secretor haplotype was an independent predictor of PMI in whites after primary coronary artery bypass graft surgery after adjustment for other covariates (P<0.02; adjusted OR: 3.97; 95% CI: 1.30 to 12.07). The combined MBL2 LYQA secretor haplotype in whites was also an independent predictor of postoperative CKMB levels exceeding 60 ng/mL (P<0.02; adjusted OR: 4.48; 95% CI: 1.95 to 16.80). Inclusion of the combined MBL2 LYQA secretor haplotype improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.715 versus 0.705).
The combined MBL2 LYQA secretor haplotype is a novel independent predictor of PMI and may aid in preoperative risk stratification of whites undergoing primary coronary artery bypass graft surgery.
genetics; myocardial infarction; immunology; inflammation; surgery
Computerized tomography is frequently employed in the critically ill, often using intravenous radiocontrast material. Many of these patients have clinical features that are considered risk factors for contrast induced nephropathy, but are simultaneously at risk for renal injury from other factors related to their acute illnesses. The attributable risk for renal dysfunction from radiocontrast exposure has not been well quantified in this population.
A prospective matched cohort study was conducted of patients scanned with or without radiocontrast enhancement while receiving intensive care in a Veterans Affairs Medical Center. Patients were matched for pre-scan measured creatinine clearance, diabetes, mechanical ventilation, and vasopressor use. Measured clearance was followed for three days after scanning. Evolution of nephropathy, as determined by change in measured clearance, was compared within matched pairs.
Fifty-three pairs of patients satisfied matching criteria. Unmatched characteristics were similar among the pairs, including serum creatinine variability during the week preceding scanning (67 ± 85% among contrast recipients, 63 ± 62% among others) and clinical risk factors for renal failure. In 29 pairs, pre-scan measured clearances were less than 60 mL/minute/1.73 m2. Following scanning, measured clearance declined by at least 33% in 14 contrast and 19 non-contrast patients (95% confidence interval for contrast associated difference in nephropathy rates -27% to 9%), while a 50% reduction in clearance persisted three days after scanning in three contrast and nine non-contrast patients (95% confidence interval for difference in rates -25% to 2%).
Among established intensive care unit patients declines in glomerular filtration following contrast-enhanced scanning are common, but these changes are far more likely to be attributable to factors other than the contrast exposure itself. The upper bound for the incidence of contrast induced renal injury lasting even three days was 2% in the population studied.
Background. Mannan-binding lectin (MBL) is involved in the development of diabetic nephropathy. MBL is a part of the innate immune system where it can activate the complement system. Serum MBL level predicts later renal impairment in diabetes patients. Direct involvement of MBL in the development of diabetic kidney disease is observed in one animal strain. However, this involvement may differ among the animal strains. We thus examined the impact of the genetic background on the role of MBL in diabetic nephropathy. Materials/Methods. C57BL/6JBomTac and 129S6/SvEvTac mice were compared. In both strains, experimental type 1 diabetes was induced in wild-type (WT) and MBL-knockout (MBL-KO) mice by streptozotocin. Nondiabetic WT and MBL-KO mice were used as controls. We tested if MBL modified the diabetes-induced kidney changes by two-way ANOVA allowing for interaction. Results. MBL aggravated diabetes-induced kidney growth and glomerulus enlargement in C57BL/6JBomTac mice. MBL did not modify diabetes effects on glomerular basement membrane thickness or mesangial volume in any strain. Diabetes-induced changes in renal gene transcription of growth factors and matrix components were unaffected by MBL. Conclusions. Strain-specific MBL effects were found on downstream diabetic kidney changes. This emphasizes the importance of genetic background in this model of diabetic complications.
To investigate the effect of pretreatment with intravenous nicorandil on the incidence of contrast-induced nephropathy (CIN) in patients with renal dysfunction undergoing coronary angiography.
Materials and Methods
This randomized controlled multicenter study enrolled a total of 166 patients (nicorandil n=81; control n=85) with an estimated glomerular filtration rate <60 mL/min. Nicorandil 12 mg dissolved in 100 mL of 0.9% saline was administered intravenously for 30 minutes just prior to coronary angiography in the nicorandil group. The same volume of only saline was given to the control group. The primary end-point was the incidence of CIN, defined as >0.5 mg/dL increase or >25% rise in serum creatinine (SCr) concentration within 48 hours of contrast exposure compared to baseline.
The final analysis included 149 patients (nicorandil n=73; control n=76). The baseline characteristics and the total volume of the used contrast (Iodixanol, 125.6±69.1 mL vs. 126.9±74.6 mL, p=0.916) were similar between the two groups. The incidence of CIN also did not differ between the nicorandil and control groups (6.8% vs. 6.6%, p=0.794). There was no difference between the two groups in the relative change in SCr from baseline to peak level within 48 hours after coronary angiography (-1.58±24.07% vs. 0.96±17.49%, p=0.464), although the nicorandil group showed less absolute change in SCr than the control group (-0.01±0.43 mg/mL vs. 0.02±0.31 mg/mL, p=0.005).
Prophylactic intravenous infusion of nicorandil did not decrease the incidence of CIN in patients with renal dysfunction undergoing coronary angiography.
Contrast media; acute kidney injury; coronary artery disease
The first line of host defense is the innate immune system that includes coagulation factors and pattern recognition molecules, one of which is mannose-binding lectin (MBL). Previous studies have demonstrated that MBL deficiency increases susceptibility to infection. Several mechanisms are associated with increased susceptibility to infection, including reduced opsonophagocytic killing and reduced lectin complement pathway activation. In this study, we demonstrate that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3 deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus infected MBL null mice developed disseminated intravascular coagulation (DIC), which was associated with elevated blood IL-6 levels (but not TNF-α and multi-organ inflammatory responses). Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest into DIC and organ failure during infectious diseases.
mannose-binding lectin; MASP; deficiency; infection; coagulation; inflammation
Mannose-binding lectin (MBL), a plasma C-type lectin, plays an important role in innate immunity. However, the interaction, and the consequences of it, between MBL and the immune system remain ill defined. We have investigated the contributing mechanisms and effects of MBL on the proliferation of human monocytes. At lower concentrations (≤4 μg/ml) MBL was shown to partially enhance monocyte proliferation. By contrast, at higher concentrations (8–20 μg/ml) of MBL, cell proliferation was markedly attenuated. MBL-induced growth inhibition was associated with G0/G1 arrest, down-regulation of cyclin D1/D3, cyclin-dependent kinase (Cdk) 2/Cdk4 and up-regulation of the Cdk inhibitory protein Cip1/p21. Additionally, MBL induced apoptosis, and did so through caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Moreover, transforming growth factor (TGF)-β1 levels increased in the supernatants of MBL-stimulated monocyte cultures. We also found that MBL-dependent inhibition of monocyte proliferation could be reversed by the TGF-β receptor antagonist SB-431542, or by anti-TGF-β1 antibody, or by the mitogen-activated protein kinase (MAPK) inhibitors specific for p38 (SB203580), but not ERK (U0126) or JNK (SP600125). Thus, at high concentrations, MBL can affect the immune system by inhibiting monocyte proliferation, which suggests that MBL may exhibit anti-inflammatory effects.
Exposure to radiocontrast media may result in acute kidney injury (AKI) or traditionally defined contrast nephropathy (CN), both of which may lead to increased morbidity and mortality. The pathogenesis of both these variants of contrast-induced nephropathy (CIN) may involve inflammatory mediators that lead to renal impairment. A link between obesity and inflammation has been clearly established, but whether obesity is independently associated with CIN is unknown.
To determine whether obesity, when stratified by body mass index (BMI), is a risk factor for CIN in a large and hemodynamically stable population of hospitalized United States veterans.
Retrospective chart review.
Presence or absence of AKI or CN after intravenous radiocontrast administration and comparison of patient characteristics between those with versus without AKI or CN.
The overall prevalence of AKI and CN was 16.1% and 12.6%, respectively. Patients with AKI or CN were comparable to those without radiocontrast injury, except that affected patients tended to be older and diabetic. When stratified by BMI, obesity was not found to be associated with the development of AKI or CN after exposure to radiocontrast.
Obesity does not appear to be an independent risk factor for AKI or CN after exposure to radiocontrast.
obesity; contrast nephropathy; kidney injury
Contrast-induced nephropathy (CIN) is the third leading cause of hospital-acquired acute kidney injury, and it is associated with poor long-term clinical outcomes. Although systolic heart failure is a well-known risk factor for CIN, no studies have yet evaluated the association between diastolic dysfunction and CIN.
We conducted a retrospective study of 735 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) and had an echocardiography performed within one month of the procedure at our institute, between January 2009 and December 2010. CIN was defined as an increase of ≥ 0.5 mg/dL or ≥ 25% in serum creatinine level during the 72 hours following PTCA.
CIN occurred in 64 patients (8.7%). Patients with CIN were older, had more comorbidities, and had an intra-aortic balloon pump (IABP) placed more frequently during PTCA than patients without CIN. They showed greater high-sensitivity C-reactive protein (hs-CRP) levels and lower estimated glomerular filtration rates (eGFR). Echocardiographic findings revealed lower ejection fraction and higher left atrial volume index and E/E’ in the CIN group compared with non-CIN group. When patients were classified into 3 groups according to the E/E’ values of 8 and 15, CIN occurred in 42 (21.6%) patients in the highest tertile compared with 20 (4.0%) in the middle and 2 (4.3%) in the lowest tertile (p < 0.001). In multivariate logistic regression analysis, E/E’ > 15 was identified as an independent risk factor for the development of CIN after adjustment for age, diabetes, dose of contrast media, IABP use, eGFR, hs-CRP, and echocardiographic parameters [odds ratio (OR) 2.579, 95% confidence interval (CI) 1.082-5.964, p = 0.035]. In addition, the area under the receiver operating characteristic curve of E/E’ was 0.751 (95% CI 0.684-0.819, p < 0.001), which was comparable to that of ejection fraction and left atrial volume index (0.739 and 0.656, respectively, p < 0.001).
This study demonstrated that, among echocardiographic variables, E/E' was an independent predictor of CIN. This in turn suggests that diastolic dysfunction may be a useful parameter in CIN risk stratification.
Contrast-induced nephropathy; Diastolic dysfunction; E/E’
To investigate the association of Mannose-binding lectin (MBL) and the MBL2 gene with type 2 diabetes and diabetic nephropathy and the influence of MBL2 polymorphisms on serum MBL levels.
The study population included 675 type 2 diabetic patients with or without nephropathy and 855 normoglycemic controls. The single nucleotide polymorphisms (SNPs) of rs1800450, rs1800451, and rs11003125 of the MBL2 gene were determined by the Multiplex Snapshot method. Serum MBL levels were measured by enzyme-linked immune sorbent assay.
Rs1800450 and rs11003125 SNPs demonstrated strong linkage disequilibrium in the study population (r2 = 0.97). The haplotypes constructed from the G allele of rs1800450 and the C allele of rs11003125 increased the risk for type 2 diabetes (OR = 1.2, 95% CI = 1.1–1.4, P = 0.01). For rs1800450, GG and GA genotypes were associated with type 2 diabetes (P = 0.02, 0.01, respectively). For rs11003125, the GC genotype frequency was significantly different between patients and controls (18.1% vs. 24.9%, P = 0.001). Analyses of genotypes and allele frequency distributions among patients with normal UAE, microalbuminuria, and macroalbuminuria showed that there was no obvious evidence of association between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels.
The rs1800450 and rs11003125 SNPs of the MBL2 gene have strong linkage disequilibrium and are associated with type 2 diabetes in the North Chinese Han population. No association was observed between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels. An association between elevated serum MBL and diabetic nephropathy was also observed.
Mannose-binding lectin (MBL) is an evolutionarily conserved protein that functions in human innate immunity by binding to microbial surfaces and promoting opsonophagocytosis. MBL has been shown to bind to Cryptosporidium sporozoites, and earlier work has suggested that the protective role of MBL may be most important in childhood. We evaluated the association between polymorphisms in the MBL gene (MBL2), serum MBL deficiency, and infection with Cryptosporidium, Entamoeba histolytica, and Giardia intestinalis in children. A large, prospective cohort of Bangladeshi preschool children was followed up for >3 years. Clinical outcomes, serum MBL levels, and MBL2 polymorphisms and haplotypes were determined. Statistically significant associations with E. histolytica and G. intestinalis were not found. Serum MBL deficiency, polymorphisms in the −221 promoter region, and the YO/XA MBL2 haplotype were strongly associated with Cryptosporidium infections, particularly recurrent infection. Children with multiple infections with Cryptosporidium were more likely to be MBL deficient (odds ratio [OR], 10.45), carry the −221 promoter variant (OR, 4.02), and have the YO/XA haplotype (OR, 4.91). We have identified a potentially important component of the human innate immune response to Cryptosporidum infection. Further work is needed to evaluate the mechanism of protection of MBL in Cryptosporidium infection.
Diabetic patients are at increased risk of cardiomyopathy, acute myocardial infarction and loss of cardiac progenitor cells (CPCs), but the aetiology is poorly understood. We hypothesised a significant role for mannose-binding lectin (MBL) in cardiomyopathies associated with hyperglycaemia.
The role of MBL in myocardial ischaemia and reperfusion (MI/R) injury was investigated in wild-type (WT) and MBL-null mice following 2 weeks of streptozotocin-induced hyperglycaemia.
Hyperglycaemic WT mice presented with significantly decreased left ventricular ejection fractions and increased serum troponin I levels and myocardial inflammation compared with non-diabetic WT mice following MI/R. Hyperglycaemic MBL-null mice or insulin-treated diabetic WT mice were significantly protected from MI/R injury compared with diabetic WT mice. In an additional study using diabetic WT mice, echocardiographic measurements demonstrated signs of dilative cardiomyopathy, whereas heart:body weight ratios suggested hypertrophic cardiac remodelling after 2 weeks of hyperglycaemia. Immunohistochemical analysis of CPCs showed significantly lower numbers in diabetic WT hearts compared with non-diabetic hearts. Insulin-treated diabetic WT or untreated diabetic MBL-null mice were protected from dilative cardiomyopathy, hypertrophic remodelling and loss of CPCs.
These data demonstrate that MBL may play a critical role in diabetic MI/R injury. Further, the absence of MBL appears to inhibit hypertrophic remodelling and hyperglycaemia-induced loss of CPCs after just 2 weeks of hyperglycaemia in mice.
Animal; Complement; Mannose-binding lectin; Type 1 diabetes
Mannose binding lectin (MBL) is an important host defence protein against opportunistic fungal pathogens. This carbohydrate-binding protein, an opsonin and lectin pathway activator, binds through multiple lectin domains to the repeating sugar arrays displayed on the surface of a wide range of clinically relevant microbial species. We investigated the contribution of MBL to antifungal innate immunity towards C. parapsilosis in vitro.
High avidity binding was observed between MBL and C. albicans and C. parapsilosis. Addition of MBL to MBL deficient serum increased the deposition of C4 and C3b and enhanced the uptake of C. albicans, C. parapsilosis and acapsular C. neoformans by polymorphonuclear cells (PMNs). Compared to other microorganisms, such as Escherichia coli, Staphylococcus aureus and Cryptococcus neoformans, C. parapsilosis and Candida albicans were potent activators of the lectin pathway.
Our results suggest that MBL plays a crucial role in the innate immunity against infections caused by yeast by increasing uptake by PMN.
Long-term lung allograft survival is limited by bronchiolitis obliterans syndrome (BOS). Mannose binding lectin (MBL) belongs to the innate immune system, participates in complement activation, and may predispose to graft rejection. We investigated mannose binding (MBL) during cold ischemia and in tissue samples from explanted lungs with BOS, and assessed MBL and complement proteins in plasma post-lung transplantation relative to BOS staging.
MBL was detected by immunohistochemistry lung tissue at the time of cold ischemia and in samples with BOS. MBL was assayed in the peripheral blood of 66 lung transplant patients transplanted between 1990–2007.
MBL localized to vasculature and basement membrane during cold ischemia and BOS. Patients further out post-lung transplant > 5 years (n = 33), had significantly lower levels of MBL in the blood compared to lung transplant patients < 5 years with BOS Op-3 (n = 17), 1738 ± 250 ng/ml vs 3198 ± 370 ng/ml, p = 0.027, and similar levels to lung transplant patients < 5 years with BOS 0 (n = 16), 1738 ± 250 ng/ml vs 1808 ± 345 ng/ml. MBL levels in all BOS 0 (n = 30) vs. all BOS Op-3 (n = 36) were 1378 ± 275 ng/ml vs. 2578 ± 390 ng/ml, p = 0.001, respectively. C3 plasma levels in BOS 0 (n = 30) vs. BOS Op-3 (n = 36) were 101 ± 19.8 mg/ml vs. 114 ± 25.2 mg/ml, p = 0.024, respectively.
MBL localizes within the lung during graft ischemia and BOS, higher levels of plasma MBL are associated with BOS Op-3 and < 5 years post-transplant, and higher level of plasma complement protein C3 was associated with BOS Op-3 clinical status. MBL may serve as a biomarker for poorer outcome post-lung transplantation.
Mannose binding lectin; Lung transplantation; Bronchiolitis obliterans syndrome
Mannose-binding lectin (MBL) deficiency due to variations in the MBL gene is associated with increased susceptibility to infections. In this study, the association between MBL deficiency and the occurrence of abdominal yeast infection (AYI) in peritonitis patients was examined. Eighty-eight patients with secondary peritonitis requiring emergency laparotomy were included. MBL genotype (wild type [WT] versus patients with variant genotypes), MBL plasma concentrations, and Candida risk factors were examined in patients with and those without AYI (positive abdominal yeast cultures during [re]laparotomy). A variant MBL genotype was found in 53% of patients with AYI and 38% of those without AYI (P = 0.18). A significantly higher proportion of variant patients had an AYI during early peritonitis (during first laparotomy) than WT patients (39% versus 16%, respectively; P = 0.012). Patients with AYI had lower MBL levels than did patients without AYI (0.16 μg/ml [0.0 to 0.65 μg/ml] versus 0.65 μg/ml (0.19 to 1.95 μg/ml); P = 0.007). Intensity of colonization (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0 to 1.1), MBL plasma concentrations of <0.5 μg/ml (OR, 4.5; 95% CI, 1.2 to 16.3), and numbers of relaparotomies (OR, 1.7; 95% CI, 1.0 to 2.8) were independently associated with AYI. In summary, deficient MBL plasma levels were independently associated with the development of AYI in patients with secondary peritonitis and seemed to facilitate early infection.
Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid β peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aβ are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.
Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy-induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA.
Serum from 216 patients with RA and 31 healthy controls participating in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) Study was collected before, during and after pregnancy. IgG galactosylation was determined by performing matrix-assisted laser desorption/ionization time of flight mass spectrometry. Disease activity was determined using the internationally recognized Disease Activity Score 28 (DAS28). MBL genotypes were determined. The pregnancy outcome measures studied were gestational age, birth weight, miscarriage and hypertensive disorders.
No association was found between the MBL genotype groups and changes in RA disease activity (P = 0.89) or changes in IgG galactosylation (patients, P = 0.75, and controls, P = 0.54) during pregnancy and in the postpartum period. Furthermore, MBL genotype groups were not related to the studied pregnancy outcome measures.
This study does not provide evidence for a role for MBL in the improvement of RA during pregnancy or for a role for MBL in pregnancy outcome.
The incidence of contrast-induced nephropathy (CIN) increases in high cardiovascular risk patients. Chronic kidney disease (CKD) is a known risk factor for CIN development. In a previous report, we demonstrated that the mean reference renal artery diameter (RVD) is an important determinant of CKD in patients undergoing coronary angiography for ischemic heart disease. However, RVD was never tested as a predictor of CIN. Aim: To look at the predictors of CIN.
A total of 218 consecutive patients undergoing coronary and renal angiography were enrolled from the cohort of the RAS-CAD study (NCT 01173666). CIN was defined as a relative increase in baseline serum creatinine ≥25% within 1 week of contrast administration.
The incidence of CIN was 22%. In a fully adjusted model, contrast medium dose (20 ml increase, OR 1.12, 95% CI 1.06–1.19, p < 0.001), iso-osmolar contrast media (OR 0.28, 95% CI 0.09–0.99, p < 0.05), atherosclerotic renovascular disease (OR 2.69, 95% CI 1.32–5.48, p < 0.05), and RVD (1 mm/1.73 m2 increase, OR 0.59, 95% CI 0.41–0.86, p < 0.05) had the greatest effect on outcome and were identified as independent predictors of CIN. CKD was selected as a predictor of CIN only in a model without RVD.
In patients undergoing coronary angiography for ischemic heart disease, RVD is a stronger predictor of CIN than CKD.
Acute renal failure; Contrast media; Iodixanol; RAS-CAD; Reference vessel diameter; Renal artery stenosis
Development of contrast-induced nephropathy (CIN), ie, a rise in serum creatinine by either ≥0.5 mg/dL or by ≥25% from baseline within the first 2–3 days after contrast administration, is strongly associated with both increased inhospital and late morbidity and mortality after invasive cardiac procedures. The prevention of CIN is critical if long-term outcomes are to be optimized after percutaneous coronary intervention. The prevalence of CIN in patients receiving contrast varies markedly (from <1% to 50%), depending on the presence of well characterized risk factors, the most important of which are baseline chronic renal insufficiency and diabetes mellitus. Other risk factors include advanced age, anemia, left ventricular dysfunction, dehydration, hypotension, renal transplant, low serum albumin, concomitant use of nephrotoxins, and the volume of contrast agent. The pathophysiology of CIN is likely to be multifactorial, including direct cytotoxicity, apoptosis, disturbances in intrarenal hemodynamics, and immune mechanisms. Few strategies have been shown to be effective to prevent CIN beyond hydration, the goal of which is to establish brisk diuresis prior to contrast administration, and to avoid hypotension. New strategies of controlled hydration and diuresis are promising. Studies are mixed on whether prophylactic oral N-acetylcysteine reduces the incidence of CIN, although its use is generally recommended, given its low cost and favorable side effect profile. Agents which have been shown to be ineffective or harmful, or for which data supporting routine use do not exist, include fenoldopam, theophylline, dopamine, calcium channel blockers, prostaglandin E1, atrial natriuretic peptide, statins, and angiotensin-converting enzyme inhibitors.
contrast-induced nephropathy; contrast media; acute kidney injury; percutaneous coronary intervention