The journal of clinical Investigation Volume 124 Number 1 January 2014
南台生技碩專二 黃國清
指導教授 林宏榮 鄭伯智
Introduction
胰臟
• 外、內分泌功能的腺體
• 胰的內分泌部分叫做胰島（蘭氏小島）
– β-細胞分泌胰島素，降低血糖，促進肝糖原的合成等作
用。
– α-細胞分泌升糖素，可以促進肝糖原分解，使血糖升高
• 胰的外分泌腺泡每天製造約1200~1500c.c.的胰液，
經由胰管送至十二指腸。胰液包括可分解蛋白質、
醣類、脂質、核酸的酵素如胰蛋白酶、胰澱粉酶、
脂酶、胰凝乳蛋白酶、胰核酸酶，以及可中和胃
酸的碳酸氫鈉。
Acute Pancreatitis (AP急性胰臟炎)
Acute Pancreatitis
Etiology and Pathophysiology
Pancreatic Ducts
become obstructed
Hypersecretion of the exocrine
enzymes of pancreas
These enzymes enter the bile duct,
where they are activated and with
bile back up into the pancreatic duct
Pancreatitis
• 過早將胰酵素活化而引起胰臟自體消化，
輕者引起胰臟輕微水腫。重者造成壞死、
出血致死可能性。
Acute Pancreatitis
Etiology and Pathophysiology
• Trypsinogen胰蛋白酶原- (a proteolytic
enzyme)
– Normally released into the small
intestine, where it is activated to trypsin
– In AP, activated to trypsin in the pancreas
causing autodigestion of pancreas
內科學誌
2013：24：162-180
臨床症狀
• 上腹痛、腹脹、發燒、嘔吐、吸收不
良、腹瀉、血糖不穩、黃疸、腹水、
呼吸窘迫或休克等。
合併症
•呼吸衰竭、腎衰竭、腸胃道出血、廣泛性
血管內凝血、出血性胰臟炎、肋膜積水、
廔管形成、假性囊腫、腹膜炎，或甚至死
亡。
Acute Pancreatitis
Complications
Pulmonary
Pleural Effusion
(enzyme induced
Inflammation of
Diaphragm)
Atelectasis
Abdominal distention
&  diaphragmatic
movement
Cardiovascular
3rd spacing
BP, HR
Vasoconstriction d/t
SNS activation
Coagulation
Renall
Immunological
Trypsin activates
both clotting
& lysing factors
 DIC & PE
Hypovolemia
GFR
Renal perfusion
Clots in renal
circulation
ATN
ARF
GI motility
bacteria outside GI
Pancreatic abscess
Necrosis
infection
11
診斷
急性胰臟炎的診斷需要下列三點中的任何兩點
( 一) 腹痛：急性發作而且持續以及劇烈的上
腹部痛，往往會擴散到背部
( 二) 血清脂肪酶或澱粉酶上升超過正常值的
三倍
( 三) 獨特的影像學檢查
急性胰臟炎的診斷與治療之最新進展:內科學誌
24：162-180
2013：
• Intraacinar activation of proteolytic
enzymes
• Microcirculatory injury
• Leukocyte chemoattraction, release of
cytokines, and oxidative stress
• One of the most feared complications of
acute pancreatitis (AP) is infection and
bacterial colonization of the necrotic
pancreas
• TLR4 activation is one of the mechanisms
by which bacterial translocation may
account for the development of severe
experimental AP
Carbon monoxide (CO)
• Carbon monoxide (CO) is increasingly
recognized as a cytoprotective and
homeostatic molecule
• The antiinflammatory and protective
properties of CO are supported by
accumulating evidence in animal models
of cardiovascular disease, inflammatory
disorders, and organ transplantation
Cardiovascular Research: Volume 41, Issue 2, 1 February 1999
• Transition metal carbonyls, termed COreleasing molecules (CO-RMs), have been
used in biological systems to deliver CO
Goal of this study
• Treatment effect of CO in AP
• Molecular biology study of CO in AP
Results
CORM-2 ameliorates
established experimental AP
• choline-deficient diet supplemented with
DL- ethionine (CDE) feeding
– severe hemorrhagic AP associated with
significant mortality
Lung myeloperoxidase (MPO)
 a measure of pulmonary leukostasis
CORM-2 suppresses systemic
proinflammatory cytokines and
TNF-α production by spleen and
pancreatic macrophages
Nature Reviews Rheumatology 4, 319-327 (June 2008)
Lineage-positive (Lin+) cells
are a mix of all cells
expressing mature cell
lineage markers. For
example for mouse bone
marrow: Mac-1 for myeloid
cells, CD4 and CD8 for Tcells, CD19 or B220 for Bcells, Ter-119 for
erythrocytes, ect. The rest of
the cells are lineagenegative (Lin-) – they are
not stained by the lineage
antibodies. All stem and
progenitor cell activity was
identified withing Linpopulation, but not in Lin+
cells.
http://stemcellassays.com/2009/11/what-islineage-negative-cells/
CORM-2 inhibits TLR4-mediated TNFα production in mouse and human
monocyte/macrophages
• Use calcium binding protein A8 (S100A8)
and HMGBl to activate TLR4
Scientific Reports 3, Article number: 2960 (2013)
Nature Reviews Rheumatology 7, 416-426 (July 2011)
http://www.invivogen.com/review-damp
Kidney International (2014) 86, 525–537.
Kidney International’s 2013 Impact Factor is 8.520
生技所碩專研一 黃國清
High-mobility group box 1 (HMGB1)
• has been recognized as an essential
damage-associated molecular pattern
(DAMP) molecule
High-mobility group box 1 (HMGB1)
• previously was thought to function only as
a nuclear factor that enhances
transcription
• recently discovered to be a crucial
cytokine that mediates the response to
infection, injury and inflammation
NATURE REVIEWS | IMMUNOLOGY: 2005(5):331-342
CORM-2 reduces macrophage
TLR4/MD2 receptor expression
during AP
Front. Immunol., 25 July 2014
CORM-2 decreases LPS
binding to TLR4/MD2 receptor
complex
Ablation of TLR4 in
hematopoietic cells confers
protection against AP
CORM-2-primed cells ameliorate
experimental AP
• caerulein hyperstimulation mild to
moderate AP
CORM-2-primed cells
ameliorate experimental AP
Carbon Monoxide (CO)一氧化碳
• Given the potential toxicity of systemically
administered CO-RMs or CO,
• the authors tested whether
monocytes/macrophages primed via
CORM-2 pretreatment
• CORM-2-primed cell transfer.
1. BM cells were isolated from Balb/c mice
2. CD11b-enriched cells were treated with
either VE or 100 μ M CORM-2 overnight.
3. PBS, 5 × 106 cells were transferred i.v. into
mice undergoing caerulein-induced
pancreatitis, 90 minutes after the first
caerulein injection
謝謝聆聽 歡迎討論