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Page 1: Clinica Pancreas

Profa. Dra. Cristina Maria Henrique PintoProfa. Adjunto do Depto. Ciências Fisiológicas-CCB-UFSC

Como citar este documento: PINTO, Cristina Maria Henrique. Fisiologia do Sistema Digestório e aplicações clínicas. Disponível em:

<http://www.cristina.prof.ufsc.br>. Acesso em: (coloque a data aqui)

Fisiologia do Sistema Fisiologia do Sistema Digestório Digestório

e aplicações clínicase aplicações clínicas

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Esta apresentação foi utilizada em minhas aulas para a

graduação em Medicina (6ª fase) até o ano de 2007. Para

que este material não se perca, deixo aqui à disposição

daqueles que eventualmente tenham interesse.

Bons estudos!

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Bibliografia básica recomendada sobre Fisiologia Humana

Livros-textos:“Berne & Levy: Fisiologia” Koeppen & Stanton, 2009,

6ª Ed. (Ed. Elsevier)“Tratado de Fisiologia Médica” Guyton & Hall, 2006,

11ª Ed. (Ed. Elsevier)“Fisiologia” Aires, M. M. 2008, 3ª Ed.

(Ed. Guanabara Koogan)“Fisiologia” Costanzo, 2007,

3ª Ed. (Ed. Elsevier)“Berne & Levy: Fundamentos de Fisiologia”, Levy et al,

2006, 4ª Ed. (Ed. Elsevier)“Fundamentos de Fisiologia Médica” Johnson, 2003

(Ed. Guanabara Koogan)“Fisiologia: texto e atlas” Silbernagl e Despopoulos, 2003

(Ed. Artmed)

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Profa. Dra. Cristina Maria Henrique PintoCFS/CCB – 6ª fase - Medicina

O Pâncreas como glândula exócrina

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Figure 3. The pancreas and adjacent anatomy.

divisões:cabeça e processo uncinado,

colo, corpo e cauda

http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&organ=4&disease=22&lang_id=1

PÂNCREASlocalização:-órgão retroperitoneal.-anteriores a ele estão o estômago, alças do intestino delgado, colon e omento

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Duct system of the pancreas. Berne et al., 2004

Ducto pancreático principal

formado a partir dos

ductos intercalares,

intralobares

extralobares

e ductos coletores principais

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Ducto pancreático:-desde a cauda até a cabeça do pâncreas-une-se ao ducto colédoco já próximo ao duodeno, formando a ampola hepatopancreática e a papila maior do duodeno (ou ampola de Vater).

http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&organ=4&disease=22&lang_id=1

É comum a existência de um ducto pancreático secundário, acessório ou dorsal (papila menor)

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Normally (90% of the time) pancreatic secretions from the entire pancreas and biliary secretions gain access to the duodenum by way of the ventral pancreatic or Wirsung’s duct because of the fusion of the dorsal pancreatic duct during embryological development.  There is only a remnant of the dorsal pancreatic or Santorini’s duct connecting to the duodenum. In 10% of individuals, fusion does not occur. This situation is called pancreas divisum. In pancreas divisum secretions from the dorsal and ventral ducts drain separately into the duodenum. Individuals with pancreas divisum may be at higher risk for pancreatitis (see Acute Pancreatitis for additional information).  Note that the distal common bile duct reaches the duodenum through the head of the pancreas.

http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1844#image

DUCTO PANCREÁTICO PRINCIPAL E DUCTO PANCREÁTICO ACESSÓRIO

(ocorrência em 90% da população)

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This figure demonstrates that the stomach, duodenum, liver, biliary system, gallbladder and pancreas are derived from closely related structures in early embryological development. The pancreas, liver, gallbladder and biliary system bud from the duodenum during early embryological development. The pancreas starts as two components, the ventral and dorsal pancreas.  In the process of development, the organs enlarge and the ventral pancreas together with the common bile duct rotates. Then, in most cases, the pancreatic duct from the dorsal pancreas fuses with the pancreatic duct from the ventral pancreas to form the main pancreatic duct. After fusion the pancreatic secretions from the entire pancreas and biliary secretions gain access to the duodenum by way of the ventral pancreatic duct.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2233#image

EMBRIOLOGIA

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Normally (90% of the time) pancreatic secretions from the entire pancreas and biliary secretions gain access to the duodenum by way of the ventral pancreatic or Wirsung’s duct because of the fusion of the dorsal pancreatic duct during embryological development.  There is only a remnant of the dorsal pancreatic or Santorini’s duct connecting to the duodenum. In 10% of individuals, fusion does not occur. This situation is called pancreas divisum. In pancreas divisum secretions from the dorsal and ventral ducts drain separately into the duodenum. Individuals with pancreas divisum may be at higher risk for pancreatitis (see Acute Pancreatitis for additional information).  Note that the distal common bile duct reaches the duodenum through the head of the pancreas.

http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1844#image

DUCTO PANCREÁTICO PRINCIPAL E DUCTO PANCREÁTICO ACESSÓRIO

(ocorrência em 90% da população)

PANCREAS DIVISUM(ocorrência em 3 a 7% da pop.)

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CAUSA de pancreatitePancreas divisum (ou pâncreas dividido)

http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&organ=4&disease=22&lang_id=1

-a mais comum anomalia congênita do pâncreas-ocorre em 3 a 7% da população-resulta em fusão incompleta ou inexistente dos brotos dorsal e ventral durante o desenvolvimento embrionário.

As regiões da cauda, corpo, colo e pequena porção da cabeça têm suas secreções drenadas para o duodeno

através da papila menor via ducto acessório.

Obstruções na papila menor podem causar pancreatite

aguda (drenagem insuficiente).

O ducto pancreático principal que esvazia-se na papila duodenal maior, drena apenas uma pequena porção da secreção exócrina pancreática (porção ventral).

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http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&organ=4&disease=22&lang_id=1

Esfíncter de Oddi:células musculares lisas que envolvem a porção terminal dos ductos biliar comume pancreático principal.

É uma estrutura dinâmica que relaxa ou contrai,

alterando as dimensões da papila maior duodenal

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http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&organ=4&disease=22&lang_id=1

Figure 7. Gallstone obstruction.

CAUSA de pancreatite agudaColelitíase

-uma das mais causas comuns de pancreatite (USA e países europeus)

-baixa mortalidade-mecanismos causais ainda não totalmente entendidos-obstrução causaria refluxo biliar nas vias pancreáticaso que desencadearia uma complexa cascata de efeitos (p. ex. ativação da tripsina nos ácinos e/ou induçãode respostainflamatória).

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The pancreas is divided into an exocrine portion (acinar and duct tissue) and an endocrine portion (islets of Langerhans). The exocrine portion, comprising 85% of the mass of the pancreas, secretes digestive enzymes, water and NaHCO3 into the duodenum. The endocrine portion, comprising 2% or less of the pancreas, secretes hormones into the blood stream.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2240#image

O PÂNCREAS: UMA GLÂNDULA ENDÓCRINA E EXÓCRINA

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?

VOLUME SECRETADO PELO

PÂNCREAS NO INTESTINO DELGADO:

1,5 L/DIA

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secreção hidro-eletrolítica

enzimas digestivas(proteases,

amilase e lipases)

Principais tipos celulares encontrados no pâncreas

Ilhotas de Langerhanshormônios: insulina (cél. β),

glucagon (cél. α), somatostatina (cél. δ) e polipeptídeo pancreático (cél. θ)

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The relationships and major features of the units of the exocrine pancreas. The pancreatic acinar cells of the acinus have prominently stained zymogen granules in the apical area of the cell.  The connecting ductule does not contain zymogen granules. The blue cell in the cartoon depicts the centroacinar cell at the border between the acinus and ductule. The centroacinar cell functions similarly to the duct cell. The major secretory products of the acinus are digestive proenzymes and enzymes with lesser amounts of water and ions. The major secretory products of the duct are water and ions.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2243#image

AS SECREÇÕES EXÓCRINAS PANCREÁTICAS: água e eletrólitos

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Neutralization of gastric acid delivered to the duodenum is necessary for optimal digestion and absorption of a meal. Several mechanisms that are not shown are involved in the neutralization process. First, the meal provides buffers from digestion of protein and triglycerides. That is, the peptides and fatty acid products act as pH buffers. Another neutralization process is absorption of hydrogen ion by the duodenal mucosa. Finally, the pancreas, biliary system and duodenal mucosa secrete bicarbonate into the duodenal lumen for neutralization.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2287#image

Importância da secreção hidroeletrolítica pancreática, rica em HCO3

-, Na+ e água na digestãoNaHCO3 + HCl NaCl + H2O + CO2 (reabsorção)

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Secreção hidroeletrolítica pancreática:grande volume e rica em Na+ e HCO3

-

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Stimulation (i.e. a meal) there is an increase in the flow rate of pancreatic secretions. Furthermore, with increasing flow rates there is a dramatic change in the concentrations of chloride and bicarbonate. The increase in bicarbonate concentration results in a secretion that is alkaline. The bicarbonate ion comes from ductal epithelial cells in the pancreas. In contrast to acinar cells, the ducts secrete a large volume of fluid with a high concentration of bicarbonate. Because the volume of secretion from the acinar cells is thought to be small compared to ductal secretion, with increasing stimulation of the pancreas the concentration of ions approaches that of the ductal secretions. Of note, the alkaline secretion of the pancreas combined with alkaline secretions from the biliary system and the duodenal mucosa neutralize the acid secretion delivered to the duodenum from the stomach. This pH neutral environment is important for optimal digestive enzyme and intestinal mucosal function.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2287#image

Composição da secreção hidroeletrolítica pancreática em razão da taxa de secreção

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Cl- secretion drives bicarbonate secretion in the pancreatic duct cell. Cl-  secretion occurs via secretin-stimulated cyclic AMP production. Cyclic AMP, in turn, activates the CFTR Cl-  secretory pathway. In the pancreatic duct cell, the Cl- may exchange with HCO3- resulting in net HCO3- secretion.  Of note, Cl-   delivered from the acinar cells also exchanges with HCO3- in the pancreatic duct. HCO3- may also enter the lumen through CFTR or by other mechanisms (see following slides). Na+ enters the duct lumen via the paracellular space to neutralize the electrical gradient created by the apical HCO3- secretion. Water follows via the paracellular space to maintain iso-osmolality. The combination of these processes determines the composition and volume of pancreatic duct secretions.

(canal regulador da condutância transmembrana da fibrose cística)

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2332#image

Mecanismos celulares de secreção de HCO3

-, Na+ e água pelas células dos ductos pancreáticos

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The two major classes chloride channels.  CFTR is activated by cAMP dependent protein kinase.  A second family of channels is regulated by calcium.  Both classes of calcium channels may be present in some cells .

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2332#image

CFTR afeta outros canais de cloreto

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CFTR activation results in activation of conductive pathways for several other molecules as listed. The mechanisms involved in the cooperative effects on transport of these molecules are not established.

canal regulador da condutância transmembrana da fibrose cística

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2332#image

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Using immunocytochemical staining of CFTR and zymogens, this image shows that CFTR is located on the apical membrane of both pancreatic duct cells and acinar cells.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2322#image

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Chloride is secreted from the apical surface of the acinar cell by two distinct transport processes. In one, agents such as cholecystokinin or muscarinic agents (i.e. acetylcholine) cause an increase in intracellular calcium that, in turn, activates a Ca+2-dependent chloride channel. In the other, agents such as secretin and VIP cause an increase in cyclic AMP that, in turn, activates a cyclic AMP-dependent chloride channel. Of note, both Ca+2 and cyclic AMP activate a basolateral K+ channel. This activation of K+ efflux facilitates apical chloride secretion by make the intracellular environment more electronegative. The Na+ /K+ ATPase is important in facilitating chloride transport because it maintains the electronegative intracellular environment as there are two K+s transported in for three Na+s transported out of the cell. Finally, the Na+/K+/Cl -Cotransport on the basolateral membrane is essential to replenish chloride secreted at the apical surface.

CFTR

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2322#image

Mecanismos celulares de secreção de Na+ e água pelas células dos ácinos pancreáticos

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Importância do conhecimento dos mecanismos celulares de secreção de HCO3

-, Na+ e água pelas células centro-acinares, ductos e ácinos

Patologias podem ocorrer quando, por diversos fatores, surgem alterações da expressão de canais e/ou

transportadores celulares.

Exemplo:

deficiência da expressão de canais de cloreto na membrana luminal celular na

fibrose cística

Primary epithelia affected in Cystic Fibrosis

Tissue affected Pancreas IntestineSweat glands

AirwaysReproductive

organs

Pathology MaldigestionMalabsorption/meconium ileus

salty sweat

Dry airways/infection

Sterility

Epithelia affected Exocrine cells Crypt epithelium

Sweat duct

Bronchial epithelium

Vas Deferens/various

Potential Therapies

Enzyme replacement

None None UTP + amiloride aerosol/gene therapy

None

http://cellscience.com/reviews2/Cystic_Fibrosis_alternative_Chloride_channel.html

acarreta deficiência nutricional especialmente na criança

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Normal trafficking of CFTR to the plasma membrane where it functions as a cAMP-dependent Cl- channel.  Mutations that lead to protein dysfunction have been classified into five categories: I-no synthesis; II-block in processing, III- block in regulation; IV – altered conductance; V – reduced synthesis. The right panel depicts the two major mechanisms of CFTR dysfunction in cystic fibrosis. The most common mutation that results in cystic fibrosis is delta508 mutation (Type II).  This leads to CFTR misfolding and degradation before it can exit the endoplasmic reticulum.  Type III and IV defects result in CFTR insertion into the membrane, but abnormal regulation.  Type I and V defects are less common causes of cystic fibrosis. Choo-Kang LR, Zeitlin PL. Curr Opin Pulm Med 2000;6:521-529

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2330#image

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The clinical manifestations of cystic fibrosis. Of note, the genetic  defects in chloride transport results in dysfunction in multiple systems including the pulmonary, hepatobiliary, pancreatic, intestinal and reproductive systems

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2322#image

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The relationships and major features of the units of the exocrine pancreas. The pancreatic acinar cells of the acinus have prominently stained zymogen granules in the apical area of the cell.  The connecting ductule does not contain zymogen granules. The blue cell in the cartoon depicts the centroacinar cell at the border between the acinus and ductule. The centroacinar cell functions similarly to the duct cell. The major secretory products of the acinus are digestive proenzymes and enzymes with lesser amounts of water and ions. The major secretory products of the duct are water and ions. http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2243#image

AS SECREÇÕES EXÓCRINAS PANCREÁTICAS: ENZIMAS

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(from duodenal epithelial cells)

-Amylase (no activation needed)

secreted by duodenal epithelium

(Enterokinase)

http://mcb.berkeley.edu/courses/mcb136/topic/Gastrointestinal

AS SECREÇÕES EXÓCRINAS PANCREÁTICAS: enzimas

lipase

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Relative amounts (by weight) of the different classes of pancreatic digestive enzymes. Proteases are the most abundant class of enzymes.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2273#image

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(from duodenal epithelial cells)

-Amylase (no activation needed)

secreted by duodenal epithelium

(Enterokinase)

http://mcb.berkeley.edu/courses/mcb136/topic/Gastrointestinal

AS SECREÇÕES EXÓCRINAS PANCREÁTICAS: enzimas

lipase

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The non-enzymatic secretory products of the acinar cell. Procolipase when activated facilitates the action of lipase. GP-2 is a glycoprotein linked to the inner zymogen granule membrane and may have a role in protein sorting or membrane recycling.  Some GP-2 is released from the zymogen granule membrane and secreted.  GP-2 is enriched in stones and may have a role in their formation. Lithostathine may prevent stone formation in the pancreas. Pancreatitis-associated protein increases with pancreatitis although the function is not known. Pancreatic secretory trypsin inhibitor has an important role in preventing intrapancreatitic zymogen activation. The ions, especially Na+ and Cl- are important for transport of the secretory products from the acinar lumen into the pancreatic ductal system by pulling water into the luminal space by osmotic forces. Water and ion flow then “wash out” the luminal space

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2273#image

AS SECREÇÕES EXÓCRINAS PANCREÁTICAS: produtos não-enzimáticos

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Action of major pancreatic lipases. The cleavage of lipids by glycerol ester hydrolase (pancreatic lipase), cholesterol ester hydrolase, and phospholipase A2 is illustrated. P, Phosphate. Berne, 2004

hidrolase de éster

de colesterol

fosfolipase A2

A secreção serosa pancreáticadigestão de lipídeos da dieta

do glicerol

hidrolase de éster

triglicerídeo

2-monoglicerídeoácido graxo

ácido graxo

éster do colesterol colesterol

ácido graxo

ácido graxo

lisolecitinalecitina

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é necessário:

- emulsificar/solubilizar os lipídeos (sais biliares hepáticos)

-formar a colipase a partir da procolipase pancreática pela tripsina

- colipase é importante pois permite a adesão da lipase pancreática aos TAGs.

Mixed micelle formed by bile salts, triacylglycerols and  pancreatic lipase.

extraído, quanto disponível, de: http://www.med.unibs.it/~marchesi/lipoprot.html

A secreção serosa pancreática: lipase e colipase

colipase

Digestão de lipídeos no ID (meio aquoso)

Produto da digestão da lipase pancreática: diacilgliceróis, monoacilgliceróis, ácidos graxos livres e glicerol

hidrolase de éster do glicerol

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Mucosal CellMucosal CellIntestinal LumenIntestinal Lumen

TGTG

LIPASELIPASE

Bile AcidsBile AcidsMicelleMicelle

MGMGFAFA

A secreção serosa pancreática: lipase e colipase

Digestão de lipídeos no ID (meio aquoso)

TG=triglyceride; MG=monoglyceride; FA=fatty acid.

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By demonstrating the relative activity of lipase action with addition of each to a mixture, these experimental results show that the activity of lipase on triglyceride hydrolysis is dependent on both bile salts and colipase. With addition of lipase alone (indicated by the green arrow) there is some triglyceride hydrolysis.  However, the addition of bile salts with colipase to a mixture of triglycerides and lipase results in the greatest activity. The importance of bile salts is that they anchor lipase and colipase together on the oil phase of trigylceride.  This “anchoring” results in the greatest activity.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2284#image

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Mucosal CellMucosal CellIntestinal LumenIntestinal Lumen

TGTG

LIPASELIPASE

Bile AcidsBile AcidsMicelleMicelle

MGMGFAFA

A secreção serosa pancreática: lipases e colipasepancreatite aguda/crônica: deficiência/ausência da lipase

pancreática digestão e absorção da gordura da dieta perda pelas fezes (esteatorréia)

esteatorréia

TG=triglyceride; MG=monoglyceride; FA=fatty acid.

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A digestão e absorção de lipídeos podem ser diminuídas por drogas que ligam-se à lipase e inibem sua ação

TG=triglyceride; MG=monoglyceride; FA=fatty acid.

Mucosal CellMucosal CellIntestinal LumenIntestinal Lumen

DROGADROGA TGTG

LIPASELIPASE

LIPASELIPASE

LIPASELIPASE

Bile AcidsBile AcidsMicelleMicelle

MGMGFAFA

A secreção serosa pancreática: lipases e colipase

esteatorréia

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A secreção serosa pancreática: alfa-amilasedigestão de amido/glicogênio

Amilopectina (amido) da batata

produtos da digestão pela α-amilase

pancreática

α-amilase pancreática

maltose dextrina-limite

ligação 1:6ligação 1:4

maltotriosealfa-amilase

Produtos da hidrólise do AMIDO pela alfa-amilase glicose

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Functions of the major brush border oligosaccharidases. The glucose, galactose, and fructose molecules released by enzymatic hydrolysis are then transported into the epithelial cell by specific transport proteins. The glucose-galactose transporter is also known as SGLT1 and the fructose transporter as GLUT5. G, Glucose; Ga, galactose; F, fructose. Berne et al., 2004

(SGLT1)

Amidoglicogênio

α-amilase pancreática

A secreção serosa pancreática: alfa-amilasedigestão de amido/glicogênio

para posterior digestão e absorção pelo epitélio do IDprodutos da digestão

pela α-amilase pancreática

α-amilase salivar

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proteases pancreáticas

PROTEÍNAS

Pepsina (gástrica)

produtos da digestão pelas proteases pancreáticas

A secreção serosa pancreática: pró-proteases digestão de proteínas/polipeptídeos

para posterior digestão e absorção pelo epitélio do ID

Amino acids Berne et al., 2004

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A secreção serosa pancreática: pró-proteases ativadas no intestino delgado pela enteropeptidase (ou enteroquinase)

Activation pathways of proenzymes by trypsin. Once trypsin is activated, it is capable of activating many other digestive proenzymes.

Como é feita a inativação da tripsina enquanto está sendo armazenada e secretada pelo

pâncreas?

Hirota et al, 2003 JOP http://www.joplink.net/prev/200303/01.html

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TRIPSINOGÊNIO + Peptídeo inibidor da tripsina

http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb46_2.html

O tripsinogênio possui, além da tripsina, o TAP (peptídeo de ativação

da tripsina), uma porção da cadeia que é removida pela enteropeptidase

somente no ID

TRIPSINOGÊNIO

Trypsin is built with an extra piece of protein chain, colored in green in the structure on the left. Actually, only two amino acids of this extra bit are seen in crystal structure, so you have to imagine the rest flopping around away from the protein. This longer form of trypsin, called trypsinogen, is inactive and cannot cut protein chains. Then, when it enters the intestine, the enzyme enteropeptidase makes one cut in the trypsin chain, clipping off the little tail. This allows the new end of the chain, colored here in purple, to tuck into the folded protein and stabilize the active form of the enzyme, as shown on the right. As extra insurance, the pancreas also makes a small protein, trypsin inhibitor (shown in red), that binds to any traces of active trypsin that might be present before it is secreted into the intestine. It binds to the active site of trypsin, blocking its action but not itself being cut into tiny pieces.

A inativação da tripsina enquanto está sendo armazenada e secretada pelo pâncreas

tripsinogênio armazenado

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Pancreatic proenzymes (also called zymogens) such as trypsinogen are converted to their active forms with cleavage and removal of an NH2 –terminal portion, the activation peptide. Removal of the activation peptide results in exposure of the catalytic site of the enzyme. In the duodenum, enterokinase activates trypsinogen while trypsin activates other zymogens.  In the case of trypsinogen, the activation peptide is known as TAP (trypsin activation peptide).  In acute pancreatitis, measurements of TAP generation can be used clinically as a predictor of severity.

Mecanismo de ativação do tripsinogênio já no ID:hidrólise pela enteropeptidase intestinal

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2280#image

Page 46: Clinica Pancreas

This graphic presents the classes of proteases in the pancreas and their sites of action. Exopeptidases cleave one amino acid at a time from the NH2-terminal or COOH-terminal of a protein. Examples are the carboxypeptidases that cleave one amino acid at a time from the COOH-terminal of a protein. Endopeptidases such as chymotrypsinogen and trypsin each cleave specific bonds irrespective of their location with respect to the NH2-terminal or COOH-terminal of the protein. http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2280#image

Ações das proteases pancreáticas

Page 47: Clinica Pancreas

Trypsin is built with an extra piece of protein chain, colored in green in the structure on the left. Actually, only two amino acids of this extra bit are seen in crystal structure, so you have to imagine the rest flopping around away from the protein. This longer form of trypsin, called trypsinogen, is inactive and cannot cut protein chains. Then, when it enters the intestine, the enzyme enteropeptidase makes one cut in the trypsin chain, clipping off the little tail. This allows the new end of the chain, colored here in purple, to tuck into the folded protein and stabilize the active form of the enzyme, as shown on the right. As extra insurance, the pancreas also makes a small protein, trypsin inhibitor (shown in red), that binds to any traces of active trypsin that might be present before it is secreted into the intestine. It binds to the active site of trypsin, blocking its action but not itself being cut into tiny pieces.

TRIPSINOGÊNIO

A inativação da tripsina enquanto está sendo armazenada e secretada pelo pâncreas

TAP (peptídeo de ativação da tripsina)porção da cadeia a mais que o

tripsinogênio possui, além da tripsina e que será removida no ID pela

enteropeptidase

tripsinogênio armazenado

Pode ocorrer uma ativação “espontânea” do tripsinogênio ainda nos ácinos ou nos ductos pancreáticos. Portanto, deve haver algum “mecanismo de segurança” para evitar que isso aconteça...

http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb46_2.html

Page 48: Clinica Pancreas

Trypsin is built with an extra piece of protein chain, colored in green in the structure on the left. Actually, only two amino acids of this extra bit are seen in crystal structure, so you have to imagine the rest flopping around away from the protein. This longer form of trypsin, called trypsinogen, is inactive and cannot cut protein chains. Then, when it enters the intestine, the enzyme enteropeptidase makes one cut in the trypsin chain, clipping off the little tail. This allows the new end of the chain, colored here in purple, to tuck into the folded protein and stabilize the active form of the enzyme, as shown on the right. As extra insurance, the pancreas also makes a small protein, trypsin inhibitor (shown in red), that binds to any traces of active trypsin that might be present before it is secreted into the intestine. It binds to the active site of trypsin, blocking its action but not itself being cut into tiny pieces.

TRIPSINOGÊNIO + PSTITRIPSINOGÊNIO

Peptídeo inibidor da tripsina (PSTI)

A inativação da tripsina enquanto está sendo armazenada e secretada pelo pâncreas

TAP (peptídeo de ativação da tripsina)porção da cadeia a mais que o

tripsinogênio possui, além da tripsina e que será removida no ID pela

enteropeptidase

tripsinogênio armazenado tripsinogênio secretado

http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb46_2.html

Page 49: Clinica Pancreas

A atividade da tripsina é controlada principalmente pelo peptídeo inibidor da tripsina, PSTI (*), sintetizado na mesma célula acinar e age como um potente inibidor natural da tripsina.

Quando o tripsinogênio é ativado no pâncreas (“espontâneo”), o PSTI liga-se à tripsina e a inativa, prevenindo assim a autodigestão celular. O PSTI também bloqueia futuras ativações

que eventualmente venham a ocorrer nos ductos pancreáticos.

A inativação da tripsina enquanto está sendo armazenada e secretada pelo pâncreas

Activation pathways of proenzymes and PAR-2 by trypsin. Once trypsin is activated, it is capable of activating many other digestive proenzymes. Trypsin also activates pancreatic and inflammatory cells via PAR-2. The trypsin activity in the pancreas is mainly controlled by PSTI. When trypsinogen is activated into trypsin in the pancreas, PSTI binds immediately to trypsin to prevent further activation of pancreatic enzymes. (PAR: protease activated receptors; PSTI: pancreatic secretory trypsin inhibitor). (*) PSTI (pancreatic secretory trypsin inhibitor) ou SPINK1 (serine protease inhibitor Kazal type 1).

Hirota et al, 2003 JOP http://www.joplink.net/prev/200303/01.html

Mutações no gene PSTI ou da

Tripsina podem promover uma predisposição à pancreatite, por

diminuir a inibição funcional da

tripsina

Page 50: Clinica Pancreas

The protective mechanisms present in the pancreas to prevent activation of zymogens in the pancreatic cell and thus prevent that damaging effects of zymogen activation.

Zymogens that have been pathologically activated in an acinar cell..http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2349#image

MECANISMOS DE PROTEÇÃO DAS CÉLULAS ACINARES CONTRA A ATIVAÇÃO INTRACELULAR DAS ENZIMAS

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Hereditary Pancreatitis: Proposed Mechanism In normal individuals there is presumed to be a continuous low-grade activation and degradation of trypsin in the pancreas. Typsin can be temporarily inactivated by binding of pancreatic secretory trypsin inhibitor (PSTI or SPINK). Both trypsinogen and PSTI are located in the zymogen granules; there is sufficient PSTI to inhibit about 10% of pancreatic trypsin. Thus, as small amounts of active trypsin are formed, PSTI binds.  Proteases, such as trypsin and mesotrypsin, can degrade trypsin.  In the most common form of Hereditary Pancreatitis (HP) the mutation may render trypsin resistant to proteolytic degradation. Thus, trypsin that escapes inhibition by PSTI may remain active and activate the other pancreatic zymogens.  Direct evidence for this mechanism is not available. http://www.gastroslides.org/main/indexcont.asp?tpc=8&mxpg=314&idxpg=73

Page 52: Clinica Pancreas

http://www.gastroslides.org/main/indexcont.asp?tpc=8&mxpg=314&idxpg=73

O PSTI (peptídeo inibidor da tripsina) LIGA-SE À TRIPSINAE A INATIVA

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The illustration in this slide shows the effect of a substitution of one amino acid (i.e. histidine for arginine) on the interaction of trypsin with pancreatic trypsin inhibitor and the function of trypsin. The illustrations indicate the proposed mechanism of hereditary pancreatitis as well. In the normal state of folding, active trypsin in the pancreas binds to the trypsin inhibitor at its active site. This interaction leads to degradation of the active trypsin. In contrast, the mutated form of trypsin has altered structure so that the trypsin inhibitor will not interact with its active site and the active trypsin will not degrade. Thus, there is an increase in active trypsin in the pancreas with the potential for causing pancreatitis. http://www.gastroslides.org/main/indexcont.asp?tpc=8&mxpg=314&idxpg=73

FORMA MUTANTE DE TRIPSINA TEM SUA ESTRUTURA ALTERADA, O PSTI (peptídeo inibidor da tripsina) NÃO INTERAGE COM SEU SÍTIO

ATIVO E A TRIPSINA NÃO É DEGRADADA.

Page 54: Clinica Pancreas

http://www.pancreas.org/assets/hp_presentation/index.htm

HP: pancreatite hereditária

Whitcomb, 2000

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ALCOOLISMO: CAUSA IMPORTANTE DE PANCREATITE CRÔNICA

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2357#image

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http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2357#image

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Mecanismos que originam a dor na pancreatite aguda

The proteinase-activated receptors (PARs) are a family of G-protein coupled receptors that, as their name suggests, are activated in a unique manner by serine proteases such as trypsin and thrombin. Recently PAR-2 has been implicated in the pathogenesis of pain. This may be particularly important in the pancreas where inflammation results in neuronal exposure to activated trypsin (from acinar cells) and

tryptase (from mast cells). Activation of PAR-2 on the peripheral processes of primary spinal afferents may have two effects. First, it may result in release of the neuropeptides CGRP and SP locally further amplifying inflammation and mast cell degranulation.  Secondly, excitation of the neurons also results in central release of neurotransmitters, leading to activation of second order neurons (as indicated by expression of the immediate early gene, c-Fos) in the dorsal horn further along in the nocioceptive pathway.  This pathway may contribute to pain experienced in both acute and chronic pancreatitis. http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2357#image

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Exocrine pancreatic secretions are regulated by both endocrine and neurocrine pathways.  In addition, the endocrine and neurocrine mediators regulating secretion differ between the acinus and the duct.  For the acinus, cholecystokinin (CCK), acetylcholine (Ach), gastrin releasing peptide (GRP), vasoactive intestinal polypeptide (VIP) and substance P regulate secretion. In humans, CCK receptors have not been found on acinar cells. However, CCK may stimulate acinar cell secretion indirectly by exciting neural pathways. For the duct, secretin and acetylcholine are the major regulators of secretion.  Serotonin may act through 5-HT receptors to regulate acinar and duct cell secretion, but the importance and mechanism of this pathway in humans has not been defined.

REGULAÇÃO DA SECREÇÃO EXÓCRINA PANCREÁTICA

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PADRÃO DA SECREÇÃO DE ENZIMAS DIGESTIVAS PANCREÁTICAS

This graphic shows the output of the digestive enzyme, trypsin, into the duodenum both during the fasting state and after a meal (dog). During fasting there are small periodic increases in trypsin output. These increases correlate with activation of the motility of the intestine during the migrating motor complex (MMC). With a meal, there is a much larger increase in trypsin output due to the inputs of several meal stimuli that mediate secretion through both neural and humoral mechanisms.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2256#image

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Neurohormonal stimulatory and inhibitory mechanisms of pancreatic secretion during cephalic, gastric, and intestinal phases involving long vagovagal and short enteropancreatic reflexes activated by CCK acting on sensory receptors on afferent nerves. Various hormonal and humoral substances stimulate or inhibit the pancreatic secretion acting either through the CNS or directly on the exocrine pancreas. Konturek et al., 2003a

Page 61: Clinica Pancreas

REGULAÇÃO DA SECREÇÃO EXÓCRINA PANCREÁTICA

estimulação neural pancreática

A presença de gordura e de ácido no duodeno estimula o SNE e as terminações aferentes sensoriais que, por sua vez, estimulam (via Vago) a atividade Parassimpática sobre a secreção pancreática

Page 62: Clinica Pancreas

Vagal afferent signals from the pancreas are processed in the nodose ganglion and the dorsal vagal complex in the CNS. Afferent signals from the pancreas as well as other afferent signals from the cephalic and gastric phases of a meal are processed in the dorsal vagal complex and efferent signals are directed to the pancreas by the vagal nerves. The vagal efferents synapse with postganglionic neurons in the pancreatic ganglia. These postganglionic neurons then mediate responses in both the islets of Langerhans and pancreatic exocrine tissue through the release of neurotransmitters such as acetylcholine (Ach). http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

REGULAÇÃO DA SECREÇÃO EXÓCRINA PANCREÁTICA

inervação pancreática

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REGULAÇÃO DA SECREÇÃO EXÓCRINA PANCREÁTICA

estimulação hormonal pancreática

A presença de gordura e de ácido no duodeno estimula a secreção endócrina intestinal das células endócrinas “S” e “I”.

As céls. “S” secretam a SECRETINA que estimula a secreção hidro-eletrolítica dos ductos pancreáticos

Page 64: Clinica Pancreas

This image shows the stimulants for release of CCK from I cells and secretin release from S cells. Of note, the I cells and S cells “taste” the specific stimulants in the lumen of the gut to activate release of the hormones. The released CCK can mediate pancreatic secretion by either activating vagal sensory afferents that results in stimulation of pancreatic acinar cell secretion though a vago-vagal reflex involving the CNS or through the circulation (i.e. hormonal action). Secretin also acts through neural (not shown) and hormonal pathways on the pancreas stimulating secretion from both ductal cells and acinar cells. http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

A REGULAÇÃO DA SECREÇÃO DOS DUCTOS PELA SECRETINA

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REGULAÇÃO DA SECREÇÃO EXÓCRINA PANCREÁTICA

estimulação hormonal pancreática

A presença de gordura e de ácido no duodeno estimula a secreção endócrina intestinal das células endócrinas “S” e “I”.

As céls. “I” secretam a CCKque estimula a secreção serosa dos ácinos pancreáticos

Page 66: Clinica Pancreas

This image shows the stimulants for release of CCK from I cells and secretin release from S cells. Of note, the I cells and S cells “taste” the specific stimulants in the lumen of the gut to activate release of the hormones. The released CCK can mediate pancreatic secretion by either activating vagal sensory afferents that results in stimulation of pancreatic acinar cell secretion though a vago-vagal reflex involving the CNS or through the circulation (i.e. hormonal action). Secretin also acts through neural (not shown) and hormonal pathways on the pancreas stimulating secretion from both ductal cells and acinar cells. http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

A REGULAÇÃO DA SECREÇÃO DOS DUCTOS PELA CCK

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The image is an electron photomicrograph of a CCK-secreting I cell. The I cell is one of the enterochromaffin cells. The apical surface of the I cell faces the lumen of the intestine where it “tastes” specific luminal nutrients (i.e. lipid). When it senses the specific nutrients, the I cell is activated and releases CCK from its basal surface. CCK can either act as a hormone to circulate to the pancreas and stimulate a secretory response or interact with sensory afferents containing CCK A (also known as CCK1) receptors. The image demonstrates the interaction of CCK with sensory receptors that are part of the enteric nervous system (ENS) of the gut. These neural receptors are located in proximity to the I cells. Vagal nerves to the CNS carry the afferent sensory signals. The afferent information going to the dorsal motor complex is processed and leads to stimulation of responses in the pancreas via vagal efferents.

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2263#image

A CCK atuaria também de maneira parácrina, estimulando as terminações sensitivas do PS (e do

SNE)

Page 68: Clinica Pancreas

The graphic in this image depicts the neurotransmission systems and neurotransmitters involved in regulating acinar and ductal secretion. The blue cell is called a centroacinar cell. These cells have characteristics more similar to ductal cells although their exact function is not known. Vagal efferents activate neurons in the intrapancreatic ganglia. Neurons from the ganglia then have processes that are in proximity to the parenchymal cells. These processes release the neurotransmitters, acetylcholine (Ach), gastrin releasing peptide (GRP) and vasoactive intestinal polypeptide (VIP) when their neurons are activated. Ach causes secretion from both acinar cells and ducts while all three neurotransmitters can cause secretion from acinar cells.

http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

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http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

Pancreatic acinar cell agonists that stimulate digestive enzyme secretion act through two separate pathways. In one pathway, agonists such as gastrin-releasing peptide, cholecytokinin and acetylcholine mediate secretion through increases in cellular calcium. In the other pathway, agonists such as vasoactive intestinal polypeptide and secretin mediate secretion through increases in cyclic AMP. Of note, a simultaneous increase in both calcium and cyclic AMP following stimulation with a combination of agonists results in a synergistic effect on secretion. That is, the observed response is greater than would be expected from the additive responses of the individual agonists acting alone. The double arrows indicate that the cellular mechanisms that cause secretion are largely unknown.http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

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toxinas de escorpiõesinseticidas organofosforados

Exposição a inseticidas organofosforados (inibidores da acetilcolinesterase) ou toxinas específicas de escorpiões causam um aumento nos níveis de liberação de acetilcolina nas terminações nervosas, podendo causar pancreatite. A picada do escorpião Tityus serrulatus também tem sido causa de pancreatite.

(G. Robles-Diaz, Mexico).

RELEVÂNCIA CLÍNICA DE TAIS CONHECIMENTOS

http://www.gastroslides.org/main/browse_deck.asp?tpc=6&mxpg=390&pg=2317#image

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Optimal digestion and absorption occur near neutral pH. Sensors in the duodenal   lumen activate pathways leading to bicarbonate secretion. The result is neutralization of acidic contents from the stomach delivered to the duodenum. The major sensor in the duodenum that mediates pancreatic bicarbonate secretion is the secretin or S cell. The apical microvilli of the S cell face the luminal contents. The S cells respond to a low pH in the duodenal lumen by releasing secretin from the basolateral region of the cell. Secretin, in turn, enters the circulation and acts as a hormone to stimulate sodium bicarbonate and water secretion from the pancreatic ducts as well as the biliary system. The threshold for secretin release and water and bicarbonate secretion is pH 4.5. Below this pH pancreatic water and bicarbonate secretion are related to the total amount of titratable acid delivered to the duodenum.  In addition to acid, other luminal factors including lipids may contribute to secretin release. http://www.gastroslides.org/main/browse_deck.asp?tpc=2&mxpg=390&pg=1842#image

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Profa. Dra. Cristina Maria Henrique PintoProfa. Adjunto do Depto. Ciências Fisiológicas-CCB-UFSC

Como citar este documento: PINTO, Cristina Maria Henrique. Fisiologia do Sistema Digestório e aplicações clínicas. Disponível em:

<http://www.cristina.prof.ufsc.br>. Acesso em: (coloque a data aqui)

Fisiologia do Sistema Fisiologia do Sistema Digestório Digestório

e aplicações clínicase aplicações clínicas

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