Dataset Information

Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.

ABSTRACT:

Introduction

Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response.

Methods

We assessed whether BMI and serum activin A levels are independent markers to determine disease severity in a cohort of patients with AP. To evaluate activin A inhibition as a therapeutic, we used a cerulein-induced murine model of AP and treated mice with activin A-specific neutralizing antibody or immunoglobulin G control, both before and during the development of AP. We measured the production and release of activin A by pancreas and macrophage cell lines and observed the activation of macrophages after activin A treatment.

Results

BMI and activin A independently predicted severe AP in patients. Inhibiting activin A in AP mice reduced disease severity and local immune cell infiltration. Inflammatory stimulation led to activin A production and release by pancreas cells but not by macrophages. Macrophages were activated by activin A, suggesting activin A might promote inflammation in the pancreas in response to injury.

Discussion

Activin A provides a promising therapeutic target to interrupt the cycle of inflammation and tissue damage in AP progression. Moreover, assessing activin A and BMI in patients on hospital admission could provide important predictive measures for screening patients likely to develop severe disease.

SUBMITTER: Thomas AL

PROVIDER: S-EPMC7263641 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.

Thomas Alexandra L AL Castellanos Karla K Mancinelli Georgina G Xia Yinglin Y Bauer Jessica J Yazici Cemal C Fantuzzi Giamila G Hwang Rosa F RF Krett Nancy L NL Papachristou Georgios I GI Whitcomb David C DC Jung Barbara B

Clinical and translational gastroenterology 20200501 5

<h4>Introduction</h4>Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response.<h4>Methods</h4>We assessed whether B ...[more]

PMID: 32358238

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Project description:ImportanceAlthough high body mass index (BMI) is associated with adverse birth outcomes, the association with severe maternal morbidity is unclear.ObjectiveTo examine the association between prepregnancy BMI and severe maternal morbidity.Design, setting, and participantsRetrospective population-based cohort study including all singleton hospital births in Washington State, 2004-2013. Demographic data and morbidity diagnoses were obtained from linked birth certificates and hospitalization files.ExposuresPrepregnancy BMI (weight in kilograms divided by height in meters squared) categories included underweight (<18.5), normal BMI (18.5-24.9), overweight (25.0-29.9), obesity class 1 (30.0-34.9), obesity class 2 (35.0-39.9), and obesity class 3 (≥40).Main outcomes and measuresComposite severe maternal morbidity or mortality included life-threatening conditions and conditions leading to serious sequelae (eg, amniotic fluid embolism, hysterectomy), complications requiring intensive care unit admission, and maternal death. Logistic regression was used to obtain adjusted odds ratios (ORs) and adjusted rate differences with 95% confidence intervals, adjusted for confounders (eg, maternal age and parity).ResultsOverall, 743 630 women were included in the study (mean age, 28.1 [SD, 6.0] years; 41.4% nulliparous). Prepregnancy BMI was distributed as follows: underweight, 3.2%; normal weight, 47.5%; overweight, 25.8%; obesity class 1, 13.1%; obesity class 2, 6.2%; and obesity class 3, 4.2%. Rates of severe maternal morbidity or mortality were 171.5, 143.2, 160.4, 167.9, 178.3 and 202.9 per 10 000 women, respectively. Adjusted ORs were 1.2 (95% CI, 1.0-1.3) for underweight women; 1.1 (95% CI, 1.1-1.2) for overweight women; 1.1 (95% CI, 1.1-1.2) for women with class 1 obesity; 1.2 (95% CI, 1.1-1.3) for women with class 2 obesity; and 1.4 (95% CI, 1.3-1.5) for women with class 3 obesity compared with women with normal BMI. Absolute risk increases (adjusted rate differences per 10 000 women, compared with women with normal BMI) were 28.8 (95% CI, 12.2-47.2) for underweight women, 17.6 (95% CI, 10.5-25.1) for overweight women, 24.9 (95% CI, 15.7-34.6) for women with class 1 obesity, 35.8 (95% CI, 23.1-49.5) for women with class 2 obesity, and 61.1 (95% CI, 44.8-78.9) for women with class 3 obesity.Conclusions and relevanceAmong pregnant women in Washington State, low and high prepregnancy BMI, compared with normal BMI, were associated with a statistically significant but small absolute increase in severe maternal morbidity or mortality.

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Project description:The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ?2/?3/?4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (? = -1.29, p = 3.97 × 10-9 ; ? = -1.38, p = 2.78 × 10-10 ; and ? = 0.58, p = 3.04 × 10-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (? = -0.63, p = 3.99 × 10-2 and ? = -0.94, p = 2.17 × 10-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (? = -1.68, p = 3.00 × 10-9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (? = -4.11, p = 2.78 × 10-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, ? = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10-1 for 3,068 individuals aged ?30 years and ? = -4.28, CI = -5.65, -2.92, p = 7.71 × 10-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ?4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.

Dataset Information

Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.

Introduction

Methods

Results

Discussion

Publications

Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.

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