Tumor necrosis factor-α and interleukin-10 contribute to immunoparalysis in patients with acute pancreatitis

Immunoparalysis, defined as downregulation of human leukocyte antigen-DR (HLA-DR) expression on monocytes, is strongly associated with septic complications of acute pancreatitis. However, the possible causes of this immunoparalysis have been largely unknown. A prospective case control study was performed in 54 patients with acute pancreatitis and 24 normal volunteers. HLA-DR expression on monocytes and serum cytokine levels were measured. In addition, monocytes from normal volunteers treated with tumor necrosis factor (TNF)-α in vitro were evaluated for HLA-DR expression and cytokine release. HLA-DR expression was significantly lower in patients with severe pancreatitis than in those with mild acute pancreatitis and healthy volunteers (42.28% ± 11.49% vs. 86.85% ± 14.56% vs. 93.92% ± 7.40%, p < 0.0001). Pearson correlation analysis showed that serum TNF-α and serum interleukin-10 levels were both correlated with HLA-DR expression. In addition, exogenous TNF-α could enhance IL-10 secretion from normal monocytes in a dose-response manner. In addition, TNF-α could downregulate the HLA-DR expression on monocytes even in the presence of anti-IL-10 antibodies. Therefore, both TNF-α and IL-10 contributed to the development of immunoparalysis in patients with acute pancreatitis.     

Pancreatic islet autotransplantation combined with total pancreatectomy for the treatment of chronic pancreatitis – the Leicester experience

Islet autotransplantation offers the potential for preventing the surgically induced diabetes that is an inevitable consequence of total pancreatectomy. This paper describes the first islet autotransplant programme in the United Kingdom and the first series in the world to use the spleen as a site for the islet graft. Over an 11 month period, 7 patients underwent total pancreatectomy for chronic pancreatitis combined with a simultaneous islet autotransplant. All 7 patients had normal glucose-tolerance levels and normal C-peptide levels pre-operatively. In 6 patients, islets were embolized into the liver via the portal vein (median transplanted volume=8.5 ml). In addition, 3 patients received islets into the splenic sinusoids via a short gastric vein (median transplanted volume=4 ml). One patient received islets into the spleen alone. One patient died of a stroke 4 weeks post transplantation. Two patients have achieved insulin independence, with a further two patients achieving ”transient” insulin independence (<1 month). The remaining 2 patients, although requiring reduced insulin doses, have not achieved insulin-independence. However, all patients have C-peptide levels within the normal range. In trying to explain these findings, split proinsulin levels were measured and found to be elevated. High levels of split proinsulin cross react with the C-peptide assay and this would explain the falsely elevated C-peptide levels. Indeed insulin levels in these patients were all below the normal range. These findings would suggest that the use of C-peptide levels as the ”gold standard” for monitoring islet autograft function, may require reappraisal.     

Chronic pancreatitis or pancreatic ductal adenocarcinoma?

The histopathologic distinction of ductal adenocarcinoma (DA) of the pancreas from chronic pancreatitis (CP) is a well-known challenge. Several parameters have been determined by the authors and other investigators to be useful in this distinction. The findings that are entirely diagnostic for DA are perineural and vascular invasion; however, they are rarely detectable in biopsy specimens. The most common findings that are highly suggestive of DC and can also be expected in biopsy specimens include random distribution of ductal structures, irregular ductal contours, nuclear enlargement (>3 times the size of a lymphocyte), and pleomorphism, distinct nucleoli, and mitosis. Other, somewhat rarer findings are uninterrupted proliferation of numerous (>50) ducts, intraluminal necrotic cellular debris, hyperchromatic raisinoid nucleoli, the presence of naked ducts in fat without surrounding pancreatic elements or fibrous tissue, and ducts lying adjacent to arterioles. Findings that favor a benign process over an invasive carcinoma are: lobular architecture with clusters of evenly spaced ductal units, uniformly sized ductal elements, smooth ductal contours, ducts surrounded by acini or islets, and intraluminal mucoprotein plugs. Combinations of these criteria should aid in the differential diagnosis of invasive ductal adenocarcinoma from benign/reactive ducts in the pancreas.     

A critical role for Akt1 signaling in acute pancreatitis progression†

Acute pancreatitis (AP) is an inflammatory disease of the pancreas that causes significant morbidity and mortality worldwide. Unfortunately, there is no specific treatment available to date. Several studies have previously shown that inhibitors of the PI3K/Akt axis downregulate the degree of inflammation in animal models of AP. However, studies on in vivo side-effects of such inhibitors are still lacking. In a recent issue of The Journal of Pathology, Chen, Malagola et al investigated if inhibition of Akt signaling plays a negative role in the regenerative phase of AP. They showed that treating AP mice with an Akt inhibitor (MK2206) impaired acinar regeneration and increased the development of acinar-to-ductal metaplasia. This is the first study to highlight the negative impact of an Akt inhibitor on cellular regeneration while simultaneously inhibiting inflammation in AP. The authors also suggested combining Akt activators to recover pancreatic regeneration. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

PKC δ mediates pro-inflammatory responses in a mouse model of caerulein-induced acute pancreatitis

Acute pancreatitis is an inflammatory disorder of the pancreas. Protein kinase C (PKC) δ plays an important role in mediating chemokine production in mouse pancreatic acinar cells. This study aims to investigate the role of PKC δ in the pathogenesis of acute pancreatitis and to explore the mechanisms through which PKC δ mediates pro-inflammatory signaling. Acute pancreatitis was induced in mice by ten hourly intraperitoneal injections of caerulein. PKC δ translocation inhibitor peptide (δV1-1) at a dose of 1.0 mg/kg or Tat (carrier peptide) at a dose of 1.0 mg/kg was administered to mice either 1 h before or 1 h after the first caerulein injection. One hour after the last caerulein injection, the mice were killed and pancreas, lungs, and blood were collected. Prophylactic and therapeutic treatment with δV1-1 attenuated caerulein-induced plasma amylase levels and pancreatic edema. Treatment with δV1-1 decreased myeloperoxidase activity and monocyte chemotactic protein-1 levels in both pancreas and plasma. PKC δ mediated acute pancreatitis by activating pancreatic nuclear factor κB, activator protein-1, and mitogen-activated protein kinases. Moreover, blockade of PKC δ attenuated lung myeloperoxidase activity and edema. Histological examination of pancreatic and lung sections confirmed protection against acute pancreatitis. Treatment with Tat had no protective effect on acute pancreatitis. Blockade of PKC δ represents a promising prophylactic and/or therapeutic tool for the treatment of acute pancreatitis.     

Helicobacter pylori infection and autoimmune diseases; Is there an association with systemic lupus erythematosus,rheumatoid arthritis,autoimmune atrophy gastritis and autoimmune pancreatitis? A systematic review and meta-analysis study

Autoimmune diseases are considered as one of the most important disorders of the immune system, in which the prolonged and chronic processes eliminate self-tolerance to the auto-antigens. The prevalence of autoimmune diseases has been increasing worldwide in the recent years. According to the literature, biological processes such as the host genome, epigenetic events, environmental condition, drug consumption, and infectious agents are the most important risk factors that make the host susceptible to the development of autoimmune diseases. In the recent years, the role of Helicobacter pylori in the induction of autoimmune diseases has attracted extensive attention. Via molecular mimicry, epitope spreading, bystander activation, polyclonal activation, dysregulation in immune response, and highly immune-dominant virulence, such as cagA, H. pylori causes tissue damage, polarity, and proliferation of the host cells leading to the modulation of host immune responses. Moreover, given the large population worldwide infected with H. pylori, it seems likely that the bacterium may develop into autoimmune diseases through dysregulation of the immune response. The frequency and relationship between H. pylori infection and systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis, and autoimmune pancreatitis were evaluated using the data from 43 studies involving 5052 patients. According to statistical analysis it is probable that infection with more virulent strains of H. pylori (such as H. pylori cagA positive) can increase the risk of autoimmune diseases. In addition, it was shown that infection with H. pylori can prevent the development of atrophic gastritis by stimulating inflammation in the gastric antrum. However, future studies should confirm the validity of this study.     

Can we expect progress in the treatment of fibrosis in the course of chronic pancreatitis?

Chronic pancreatitis (CP) is a necroinflammatory process characterized by loss of both exocrine and endocrine function. To date, the disease has been treated symptomatically. Real advances in CP management can be expected once the pathophysiology of the disease is elucidated and individual stages of its development are properly managed. A key role in the CP pathogenesis is played by activation of pancreatic stellate cells (PSCs) that cooperate with the remaining pancreatic cells. All these cells produce cytokines, growth factors, angiotensin and other substances, which paracrinally or autocrinally induce further, persistent activation of PSCs. The activated PSCs are capable of producing and modifying the extracellular matrix. An optimal therapeutic preparation should exert beneficial effects on all the above-mentioned phenomena observed in CP. The most promising treatment modalities include blocking of the renin-angiotensin system (RAS), activation of peroxisome proliferator-activated receptors gamma (PPAR-γ), influence on the remaining PSC signaling pathways, blocking of substances produced by activated PSCs, and antioxidants. The findings of many recent experimental studies are highly encouraging; however, their efficacy should be confirmed in well-designed clinical trials.     

Should patients with polycystic ovarian syndrome be treated with metformin?

The recognition of insulin resistance as a principal factor in the pathogenesis of polycystic ovarian syndrome (PCOS) has led to the use of insulin-lowering agents, also called 'insulin-sensitizing drugs', for its treatment. The most extensively studied insulin-lowering agent in the treatment of PCOS is metformin: an oral antihyperglycaemic agent used initially in the treatment of type 2 diabetes mellitus. Metformin is effective in the treatment of PCOS-related anovulation and infertility. Moreover, preliminary evidence indicates that metformin may also be effective in decreasing the risk of early spontaneous miscarriage in women with PCOS. Metformin also appears to induce cardioprotective effects on serum lipids as well as plasminogen activator inhibitor (PAI)-1 and may decrease the risk of development of type 2 diabetes. The highly promising therapeutic profile of metformin is related to the role of this agent in controlling an important aetiologic factor in the pathogenesis of PCOS: hyperinsulinaemia.     

Time course of malonic dialdehyde and α-tocopherol in rat pancreas during the first hours of acute pancreatitis

Time course of malonic dialdehyde and α-tocopherol levels in rat pancreas during the first day of experimental pancreatitis indicates activation of lipid peroxidation and components of the antioxidant system in the involved organ. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 129, No. 5, pp. 536–538, May, 2000     

Clinical Experience with Growth Hormone Treatment in Patients with β-Thalassaemia Major

The aetiology of the growth retardation occurring in patients with beta-thalassaemia major is considered to be multifactorial. Although growth hormone (GH) secretion appears to be normal in many thalassaemic patients with short stature, there is evidence indicating impaired GH secretion in approximately 3% of patients. The response to recombinant human GH treatment (rHGH) is not predictable, based on either the parameters known to affect the response to treatment or the type of defect in the GH-insulin-like growth factor (IGF-1) axis. The wide variation in growth velocity observed during rHGH treatment suggests that treatment with the usual dose of rHGH (0.6 U/kg/week) cannot be considered effective in all patients, although rHGH has been successful in some patients. Therefore further studies are required in order to evaluate the effects of supraphysiological doses of rHGH on growth. Since these patients are prone to develop abnormal glucose homeostasis, oral glucose tolerance tests must be performed periodically during rHGH treatment.