Specific Therapy for Local and Systemic Complications of Acute Pancreatitis With Monoclonal Antibodies Against ICAM-1

Werner, Jens; Z’graggen, Kaspar; Castillo, Carlos Fernández‐del; Lewandrowski, Kent; Compton, Carolyn C.; Warshaw, Andrew L.

doi:10.1097/00000658-199906000-00010

Cited by 120 publications

(92 citation statements)

References 35 publications

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“…The thymosin β4 treatment markedly reduced the increase in pancreatic MPO activity at 6 to 12 h after acute pancreatitis, which suggests a significant reduction in neutrophil infiltration into the pancreatic tissues. The finding that thymosin β4 markedly reduced neutrophil infiltration is consistent with a previous report demonstrating that treatment with anti-ICAM-1 antibody decreased leukocyte infiltration in pancreas and attenuated tissue damage (44).…”

Section: A B C Dsupporting

confidence: 92%

Effects of thymosin β4 on a rat model of severe acute pancreatitis

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the effects of thymosin β4 on a rat model of severe acute pancreatitis (SAP) induced by sodium taurocholate (STC) and the underlying mechanism. SAP was induced by the retrograde infusion of 5% STC (1 ml/kg) into the bile-pancreatic duct. In certain rats, thymosin β4 (30 mg/kg) was administered intraperitoneally 30 min prior to the infusion of STC. The severity of pancreatitis was evaluated by the measurement of serum amylase, lipase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) levels, and histological grading. Nuclear factor (NF)-κB activation was evaluated by immunohistochemistry and western blot analysis. Intercellular adhesion molecule (ICAM)-1 protein expression in the pancreas was studied using western blot analysis. Prophylactic administration of thymosin β4 was found to attenuate serum amylase and lipase activity and the serum concentrations of proinflammatory cytokines. In addition, it attenuated pathological pancreatic injury, pancreatic MPO activity, and the activation of NF-κB and ICAM-1 in the pancreas. These results suggest that thymosin β4 exerts a protective effect against STC-induced pancreatic injury. IntroductionAcute pancreatitis is an inflammatory disease of the pancreas characterized by acute abdominal pain and increased concentrations of serum amylase and lipase. In the majority of cases, it runs a mild course without complications. However, ~25% patients develop severe acute pancreatitis (SAP), which may result in systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome, and the mortality rate is up to 40% (1,2). In recent years, many investigators have attempted to reveal the pathogenesis of acute pancreatitis; however, the exact mechanisms are not well understood. Accumulating evidence indicates that SAP is closely associated with tissue injury and microcirculation disorders resulting from the production of proinflammatory cytokines and mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and intercellular adhesion molecule (ICAM)-1 (3,4). In addition, studies have shown that acute pancreatitis can lead to activation of the nuclear factor (NF)-κB signaling pathway (5,6). Therefore, reducing the levels of proinflammatory cytokines and adhesion molecules to block the inflammatory cascade may be a valid treatment strategy for acute pancreatitis.Thymosin β4 is a highly conserved polypeptide that was originally isolated from bovine thymus gland extract in 1981 (7). Thymosin β4 contains 43-amino acid residues with a molecular weight of 4964.5 Da and an isoelectric point of 4.6 (8). It is widely distributed in many tissues and cell types and is found in high concentrations in blood platelets, macrophages and white blood cells, but not in red blood cells (9). The most prominent physiological role of thymosin β4 as the major actin-sequestering peptide contributes to the regulation of actin polymerization in mammalian nucleated cells (10). There is g...

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Section: A B C Dsupporting

confidence: 92%

Effects of thymosin β4 on a rat model of severe acute pancreatitis

et al. 2015

Experimental and Therapeutic Medicine

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“…It is known that ICAM-1 plays a significant role in leukocyte infiltration of the pancreas and that anti-ICAM-1 antibody therapy decreases acinar cell damage in experimental pancreatitis [54,55]. Also, Nerin et al showed the therapeutic effectiveness of chimeric TNF antibody, infliximab [56].…”

Section: Discussionmentioning

confidence: 99%

TNF-α Regulated MAdCAM-1 Expression in Pancreatic Microvessel Endothelium: A Possible Role for MAdCAM-1 in Pancreatitis?

Ando¹,

Jordan²,

Wang³

et al. 2008

TOGASJ

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Abstract:The Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) is associated with active inflammatory bowel disease; however MAdCAM-1 expression in the pancreas has not been previously documented. This study investigated MAdCAM-1 expression during cerulein-induced pancreatitis, and examined MAdCAM-1 expression, regulation and function in cytokine-treated pancreatic endothelial cells. Acute pancreatitis was induced by serial injections of cerulein over 10h, at which point tissue samples were collected. Pancreas endothelial cells (PMEC) were prepared from H2Kb-tsA58 (Immortomouse) mice. MAdCAM-1 expression was examined by immunoblotting after cytokine (TNF-, ILor IFN-) stimulation. 2 nd messages regulating MAdCAM-1 were studied by adding pharmacological blockers prior to cytokines. MAdCAM-1 dependent lymphocyte adhesion was monitored using 4 7-integrin expressing lymphocytes. In cerulein-pancreatitis, MAdCAM-1 was upregulated by 10h, and closely correlated with histopathology. In PMEC, only TNF-induced MAdCAM-1 dose (0-20ng/ml) and time (>12h-48h) dependently. MAdCAM-1 expression was PKC, tyrosine kinase, p38 MAPK, and NF-B-PARP dependent. PMEC-lymphocyte adhesion was increased by TNF-, and significantly reduced by MAdCAM-1 antibody. MAdCAM-1 is induced in the inflamed pancreas, and in TNF-stimulated PMEC, and may represent a novel determinant of pancreatic-lymphocyte recruitment in inflammation. PMEC cells might provide a useful system to study mechanisms related to both acute and chronic pancreatitis.

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“…Ïðèãí³-÷åííÿ ICAM-1 ïîë³ïøóº ì³êðîöèðêóëÿö³þ ï³äøëóíêîâî¿ çàëîçè ³ çàïîá³ãàº âèíèêíåííþ áëèñêàâè÷íîãî çàïàëåííÿ òà íåêðîçó [19,29].…”

Section: òàáëèöÿunclassified

The Role of Proinflammatory Cytokines and Adhesion Molecules in Vascular Disorders and Organ Dysfunction in Acute Pancreatitis Patients

Chooklin¹,

Hranat²

2013

Lʹviv. klin. visn.

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Âñòóï. Çàõâîðþâàí³ñòü íà ãîñòðèé ïàí-êðåàòèò (ÃÏ) ó ñâ³ò³ çðîñòàº âïðîäîâae îñòàí-í³õ ðîê³â, ãîëîâíèì ÷èíîì ÷åðåç ñïîaeèâàí-íÿ àëêîãîëþ [10,32].Âàaeêèé ÃÏ õàðàêòåðèçóºòüñÿ âèíèêíåí-íÿì ïàíêðåîíåêðîçó, ì³ñöåâèìè óñêëàäíåí-íÿìè òà ñèñòåìíîþ îð´àííîþ äèñôóíêö³ºþ [1,17] ³ ñòàíîâèòü áëèçüêî 20,0 % óñ³õ âè-ïàäê³â ÃÏ.Íåçâàaeàþ÷è íà óñï³õè â ³íòåíñèâí³é òå-ðàï³¿, ðàííÿ ñìåðòí³ñòü â³ä ÃÏ çàëèøàºòüñÿ âèñîêîþ [5,17].Ïåðåä÷àñíà àêòèâàö³ÿ âíóòð³øíüîêë³òèí-íèõ ïðîòåàç ï³äøëóíêîâî¿ çàëîçè â³äîìà ÿê îäíà ç íàéðàí³øèõ ïîä³é ó ïàòî´åíåç³ ÃÏ [28] Îñíîâíà ëàíêà â ïàòî´åíåç³ ÃÏ ïåðåõ³ä â³ä ì³ñöåâîãî çàïàëåííÿ äî ñèñòåìíîãî, ùî çóìîâëþº âàaeê³ñòü ïåðåá³ãó çàõâîðþâàííÿ. Ìåä³àòîðè çàïàëüíî¿ â³äïîâ³ä³, ÿêèõ ñèíòå-çóþòü àêòèâîâàí³ ìàêðîôà´è, íåéòðîô³ëè òà ³íø³ êë³òèíè îð´àí³çìó, º âèçíà÷àëüíèìè ó âèíèêíåíí³ ÑÑÇÂ, ùî õàðàêòåðèçóº ïî÷àò-êîâ³ ñòàä³¿ ÃÏ, òà ó ïîñèëåíí³ çàïàëüíèõ çì³í ó ï³äøëóíêîâ³é çàëîç³ é ïðèëåãëèõ òêàíèíàõ. Åêñïåðèìåíòàëüí³ òà êë³í³÷í³ ñïîñòåðåaeåííÿ ïîêàçóþòü, ùî ïðîçàïàëüí³ öèòîê³íè çàëó÷åí³ äî âèíèêíåííÿ ì³ñöåâèõ ³, îñîáëèâî, ñèñòåìíèõ óñêëàäíåíü ó õâîðèõ íà ÃÏ [1,5,9].Çì³íè ó ñïëàíõí³÷íèõ àðòåð³ÿõ çà ãîñòðî-ãî íåêðîòè÷íîãî ïàíêðåàòèòó º íàñë³äêîì âèâ³ëüíåííÿ ïðîçàïàëüíèõ öèòîê³í³â ³ âàçî-àêòèâíèõ ìåä³àòîð³â, ÿê³ çàëó÷àþòü äî ïàòî-ëî´³÷íîãî ïðîöåñó ëåéêîöèòè é àêòèâóþòü åíäîòåë³é ñóäèí. Óñå öå ïðèçâîäèòü äî åíäî-òåë³àëüíî¿ ³ ì³êðîöèðêóëÿö³éíî¿ äèñôóíê-ö³¿. Âîäíî÷àñ â³ëüí³ ðàäèêàëè êèñíþ òà åêñ-ïðåñ³ÿ ìîëåêóë àä´åç³¿ ñïðè÷èíþþòü ñòàç ó äð³áíèõ ñóäèíàõ. Ïîðóøåííÿ ì³êðîöèðêó-ëÿö³¿ º âàaeëèâèì êðîêîì â³ä ëåãêîãî (çáåðå-aeåíà ì³êðîöèðêóëÿö³ÿ, íàáðÿêîâèé ïàíêðå-àòèò) äî âàaeêîãî ïåðåá³ãó çàõâîðþâàííÿ.Ï³ñëÿ ïî÷àòêó ÃÏ çáåðåaeåííÿ àáî íîðìà-ë³çàö³ÿ ì³êðîöèðêóëÿö³¿ ï³äøëóíêîâî¿ çàëî-çè ìîaeå çàïîá³ãòè ïîäàëüøîìó íåêðîçó òêà-íèí, ùî ñïðèÿº çìåíøåííþ óñêëàäíåíü ³ ëå-òàëüíîñò³.Ìåòà äîñë³äaeåííÿ: âèçíà÷èòè ïàòî´åíå-òè÷íó ðîëü ïðîçàïàëüíèõ öèòîê³í³â, ìîëå-êóë àä´åç³¿ ³ Å-ñåëåêòèíó ó âèíèêíåíí³ ñó-äèííèõ ïîðóøåíü ³ îð´àííî¿ äèñôóíêö³¿ ó õâîðèõ íà ãîñòðèé íåêðîòè÷íèé ïàíêðåàòèò. Ìàòåð³àëè ³ ìåòîäè äîñë³äaeåííÿ. Îáñòå-aeåíî 53 õâîðèõ (ae³íîê 20, ÷îëîâ³ê³â 33 ó â³ö³ â³ä 20 äî 77 ðîê³â) íà ÃÏ ï³ä ÷àñ øïè-òàë³çàö³¿ ³ 17 ïðàêòè÷íî çäîðîâèõ îñ³á (êîí-òðîëüíà ´ðóïà), òîòîaeíèõ çà â³êîì ³ ñòàòòþ. Ä³à´íîç ÃÏ ´ðóíòóâàâñÿ íà ðåçóëüòàòàõ îá-ºêòèâíîãî îáñòåaeåííÿ, á³îõ³ì³÷íèõ ïîêàçíè-êàõ (êîíöåíòðàö³ÿ ïàíêðåàòè÷íî¿ àì³ëàçè ³ ë³ïàçè ïåðåâèùóâàëà ðåôåðåíòí³ ëàáîðàòîð-

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Specific Therapy for Local and Systemic Complications of Acute Pancreatitis With Monoclonal Antibodies Against ICAM-1

Cited by 120 publications

References 35 publications

Effects of thymosin β4 on a rat model of severe acute pancreatitis

Effects of thymosin β4 on a rat model of severe acute pancreatitis

TNF-α Regulated MAdCAM-1 Expression in Pancreatic Microvessel Endothelium: A Possible Role for MAdCAM-1 in Pancreatitis?

The Role of Proinflammatory Cytokines and Adhesion Molecules in Vascular Disorders and Organ Dysfunction in Acute Pancreatitis Patients

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