Alteration of Bioenergetics in Pancreatic Pathophysiology

Michelle Gray, Department of Pharmacology, University of Kiel, Kiel, Germany, Email: graymichelle@gmail.com

Received: 17-Jun-2024, Manuscript No. AJPBP-24-144293; Editor assigned: 19-Jun-2024, Pre QC No. AJPBP-24-144293 (PQ); Reviewed: 04-Jul-2024, QC No. AJPBP-24-144293; Revised: 12-Jul-2024, Manuscript No. AJPBP-24-144293 (R); Published: 19-Jul-2024

Description

A fundamental aspect of acute pancreatitis is mitochondrial dysfunction that is Ca²⁺-dependent. Supramaximal stimulation causes damaging global, sustained calcium elevations, in contrast to the spatially restricted, oscillatory Ca²⁺ signalling events that occur in response to physiological levels of secretagogues in isolated pancreatic acinar cells [1-3].

A primary pathological feature that is shared by known acute pancreatitis precipitants, such as bile acids, non-oxidative ethanol metabolites, and fatty acids, is the capacity to overload cytosolic Ca²⁺ and, as a result, disrupt Ca²⁺ homeostasis in acinar cells. It is also an important trigger for mitochondrial damage that compromises cellular ATP production [4,5]. Although in vivo studies have yielded somewhat varying results, it has long been recognized that the pancreas' altered energy levels are relevant to its pathology. Using non-invasive 31P NMR spectrometry, it was discovered in early 1990 that experimental AP models had significant decreases in cellular ATP in the pancreas. It's interesting to note that responses varied depending on the model used. Consequently, levels of ATP remained constant in caerulein hyper stimulation and partial ductal obstruction models, whereas significant falls were observed in AP induced by fatty acid (oleic acid) infusion or regional ischemia. W conducted a subsequent investiga    tion. Using a Clark-type electrode, Halangk and colleagues demonstrated a decrease in phosphorylating respiration in acinar cells and a decrease in ATP to 57% in caerulein AP after 24 hours, supporting these findings. It is important to note that this phenomenon developed relatively slowly. For example, the cellular ATP content reported at early time points (up to 5 hours) was not significantly lower than that of controls, making it develop slower than other symptoms of experimental acute pancreatitis like vacuolization and intracellular trypsinogen activation [6-9].

In contrast, a recent study found that mitochondria were damaged before trypsinogen and NFkB were activated by high levels of L-lysine. This damage could have been caused by an imbalance between hydrolysis and ATP synthesis or an impairment in electron transport chain coupling. The majority of in vivo models have shown that acute pancreatitis is accompanied by a loss of pancreatic ATP. This suggests that early mitochondrial damage is a crucial factor in the progression of the disease [10]. Variation between studies may be due to methodological differences, the severity of the experimental model, or both. Further comparative studies are needed. As a result, the in vivo findings are consistent with ATP measurements made on isolated acinar cells, which showed that the concentration of ATP in cells treated with fatty acid (POA) or bile acid (TLC-S) decreased rapidly.

As a result, changes in oxygen supply and nutrient availability determined by the microcirculation will be "superimposed" on the intrinsic abilities of the exocrine cells to adjust metabolism and signalling in response to secretagogues and the inducers of acute pancreatitis discussed in the previous section. Isolated pancreatic acinar cells have been used to investigate the mechanisms underlying the ATP depletion caused by acute pancreatitis precipitants. Studies using confocal microscopy revealed that acinar cells overloaded with Ca²⁺ led to a rapid depolarization of the mitochondrial membrane potential, decreased NAD (P) H levels, increased FAD+ levels, and necrosis. In accordance with stimulus-metabolism coupling (as previously mentioned), the bile acid TLCS caused predominantly oscillatory calcium rises and NADH elevations when applied at a lower concentration (200 M). However, NAD (P) H significantly decreased when sustained Ca²⁺ elevations at higher concentrations (500 M) occurred. In a similar vein, the non-oxidative ethanol metabolite Palmit-Oleic Acid Ethyl Ester (POAEE) and POA, both of which were produced by hydrolysis of the fatty acid ethyl ester, elevated cytosolic Ca²⁺ levels for an extended period of time and led to the dysfunction of mitochondria. The temporal relationship between these events was revealed by measuring cytosolic Ca²⁺ and m simultaneously; as cytosolic Ca²⁺ increased, mitochondrial depolarization and a rapid decrease in NAD(P)H were mirrored. Magnesium Green was used to measure the significant depletion of intracellular ATP that occurred as a result of mitochondrial dysfunction. The protonophore CCCP had no effect beyond its maximum. Pre-treatment with the Ca²⁺ chelator BAPTA, which prevented the loss of m while maintaining a decrease in NAD(P)H, revealed a curiously Ca²⁺-independent action of POA. In contrast to excitable cells like cardiomyocytes, the contribution of the Na+/Ca²⁺ exchanger to Ca²⁺ homeostasis in the pancreatic acinar cell appears weak or absent. The rundown of mitochondrial ATP production has significant effects on Ca²⁺ homeostasis in the pancreatic acinar cell, which appears particularly vulnerable to sustained cytosolic Ca²⁺ increases. During the course of the development of acute pancreatitis, the major pathways for Ca²⁺ clearance, the SERCA and PMCA pumps, which are powered by cellular ATP, would experience progressive impairment as energy levels decreased. Ca²⁺ dependent mitochondrial dysfunction likely perpetuates sustained cytosolic Ca²⁺ elevation, leading to increased necrotic cell death in a vicious cycle. The provision of intracellular ATP through a patch pipette demonstrated the significance of maintaining ATP levels for acinar cell function. This prevented the harmful Ca²⁺ elevations induced by POA, confirming the significance of the SERCA/PMCA for Ca²⁺ clearance in pancreatic acinar cells. As a result, bile acid-induced sustained Ca²⁺ rises and acinar cell necrosis were prevented by ATP, and the adverse effects of ethanol and its non-oxidative metabolites on CFTR in ductal cells that contribute to acute pancreatitis were mitigated by ATP supplementation.

References

1. Kline RM, Kline JJ, Di Palma J, Barbero GJ. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr. 2001;138(1):125-128.

   [Crossref] [Google Scholar] [Pubmed].

2. Massironi S, Cavalcoli F, Rausa E, Invernizzi P, Braga M, Vecchi M. Understanding short bowel syndrome: Current status and future perspectives. Dig Liver Dis. 2020;52(3):253-261.

   [Crossref] [Google Scholar] [Pubmed].

3. Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology. 2003;124(4):1111-1134.

   [Crossref] [Google Scholar] [Pubmed].

4. Scolapio JS. Short bowel syndrome: recent clinical outcomes with growth hormone. Gastroenterology. 2006;130(2):S122-S126.

   [Crossref] [Google Scholar] [Pubmed].

5. Spencer AU, Neaga A, West B, Safran J, Brown P, Btaiche I, et al. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg. 2005;242(3):403.

   [Crossref] [Google Scholar] [Pubmed].

6. Vanderhoof JA, Langnas AN. Short-bowel syndrome in children and adults. Gastroenterology. 1997;113(5):1767-1778.

   [Crossref] [Google Scholar] [Pubmed].

7. Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, et al. Reversal of parenteral nutrition–associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006;118(1):e197-e201.

   [Crossref] [Google Scholar] [Pubmed].

8. Jeejeebhoy KN. Management of short bowel syndrome: avoidance of total parenteral nutrition. Gastroenterology. 2006;130(2):S60-S66.

   [Crossref] [Google Scholar] [Pubmed].

9. Kuck KH. Arrhythmias and sudden cardiac death in the COVID-19 pandemic. Herz. 2020 ; 45(4):325-326.

   [Crossref] [Google Scholar] [Pubmed]

10. Mehra R. Global public health problem of sudden cardiac death. J Electrocardiol. 2007;40(6):S118- S122.

    [Crossref] [Google Scholar] [Pubmed].