section vii: digestion, absorption, and metabolism · section vii: digestion, absorption, and...

Chapter 42: Gastrointestinal Motility 469

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and interlobular ducts until finally the secretions reach the oral pharynx (Figure 42.2). The secretions of individual salivary glands range from a watery composition referred to as a serous secretion to a more mucoid secretion. For instance in the dog the parotid gland produces a serous secretion laden with amy-lase, which begins the process of starch digestion, and buffers to help control the pH of the ingesta. A lipase enzyme is also pre-sent to initiate fat digestion. Serous glands also secrete IgA and antibacterial substances such as lysozyme that also help keep bacterial numbers in check within the oral cavity. The sublin-gual glands of a dog produce a mucus‐type saliva. The mucin helps lubricate the bolus as it passes down the esophagus. The submaxillary gland of the dog produces a mixed secretion that has both serous and mucous attributes. A 20‐kg dog produces approximately 0.5–1 L of saliva daily, more when fed a dry dog food. All saliva is hypotonic to help reduce the osmotic concentration of the ingesta.

Salivary secretions are under the control of the glossopha-ryngeal nerve (parotid glands) and the facial nerve (submaxil-lary and sublingual glands). These nerves carry parasympathetic fibers and it is the parasympathetic tone that determines the rate of saliva production and secretion. Secretion occurs when myoepithelial cells (a type of epithelial cell that is able to contract) respond to parasympathetic stimulation and squeeze the acinus to propel saliva down the ducts. There is no sympathetic innervation of the salivary glands. As Pavlov demonstrated, higher centers of the brain can activate parasympathetic pathways to cause a dog to drool in anticipa-tion of a meal. In ruminants, saliva composition can also be altered to help the animal maintain rumen pH at a more constant level. When actively chewing, the pH of ruminant

saliva can increase to about 8.5. In an adult cow the amount of saliva secreted can be 100–180 L daily.

In all species, the cells lining the striated ducts of the salivary glands are capable of increasing secretion of sodium and potassium into the saliva to increase its alkalinity in order to enhance its buffering activity. These cells increase saliva pH in response to a hormone called secretin. Secretin is produced by enteroendocrine cells within the duodenum when the pH of the duodenum decreases.

Deglutition (swallowing)

Once the bolus of food has been chewed and is moistened by saliva and moved to the back of the oral cavity it is ready to be swallowed. Deglutition or swallowing is a highly complex reflex that must deliver ingesta or fluids to the esophagus while keeping such material out of the respiratory tract. Keep in mind that the pathway of airflow into the trachea and the pathway for food entering the esophagus intersect within the pharynx. The first step in swallowing is voluntary: the animal uses motor neurons to push the bolus of food to the back of the tongue. Pharyngeal receptors sense the presence of the bolus and afferent fibers of cranial nerves V, IX and X carry this information to the medulla. From this point on, the swallowing reflex is involuntary.

Myoepithelialcells

Acinar cells

Proteinmucus

Intercalatedduct cells

Striated duct cells

Alkaline solution

Acinus

Figure 42.2 Photomicrograph of a salivary gland. Acinar cells produce proteins and antibacterial peptides. Secretion is stimulated by parasympathetic fibers that enhance metabolic activity of acinar cells and also stimulate contraction of myoepithelial cells to expel fluid into ducts. The ducts add an alkaline secretion to the saliva in response to the hormone secretin synthesized in the duodenum.

1 The pathway for food and air cross each other. Describe the steps taken to insure that food does not enter the trachea or the nasopharynx.

Secre%na

Páncreas

CCK

Grasas Aminoácidos Duodeno

SEE

Chapter 42: Gastrointestinal Motility 469

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and interlobular ducts until finally the secretions reach the oral pharynx (Figure 42.2). The secretions of individual salivary glands range from a watery composition referred to as a serous secretion to a more mucoid secretion. For instance in the dog the parotid gland produces a serous secretion laden with amy-lase, which begins the process of starch digestion, and buffers to help control the pH of the ingesta. A lipase enzyme is also pre-sent to initiate fat digestion. Serous glands also secrete IgA and antibacterial substances such as lysozyme that also help keep bacterial numbers in check within the oral cavity. The sublin-gual glands of a dog produce a mucus‐type saliva. The mucin helps lubricate the bolus as it passes down the esophagus. The submaxillary gland of the dog produces a mixed secretion that has both serous and mucous attributes. A 20‐kg dog produces approximately 0.5–1 L of saliva daily, more when fed a dry dog food. All saliva is hypotonic to help reduce the osmotic concentration of the ingesta.

Salivary secretions are under the control of the glossopha-ryngeal nerve (parotid glands) and the facial nerve (submaxil-lary and sublingual glands). These nerves carry parasympathetic fibers and it is the parasympathetic tone that determines the rate of saliva production and secretion. Secretion occurs when myoepithelial cells (a type of epithelial cell that is able to contract) respond to parasympathetic stimulation and squeeze the acinus to propel saliva down the ducts. There is no sympathetic innervation of the salivary glands. As Pavlov demonstrated, higher centers of the brain can activate parasympathetic pathways to cause a dog to drool in anticipa-tion of a meal. In ruminants, saliva composition can also be altered to help the animal maintain rumen pH at a more constant level. When actively chewing, the pH of ruminant

saliva can increase to about 8.5. In an adult cow the amount of saliva secreted can be 100–180 L daily.

In all species, the cells lining the striated ducts of the salivary glands are capable of increasing secretion of sodium and potassium into the saliva to increase its alkalinity in order to enhance its buffering activity. These cells increase saliva pH in response to a hormone called secretin. Secretin is produced by enteroendocrine cells within the duodenum when the pH of the duodenum decreases.

Deglutition (swallowing)

Once the bolus of food has been chewed and is moistened by saliva and moved to the back of the oral cavity it is ready to be swallowed. Deglutition or swallowing is a highly complex reflex that must deliver ingesta or fluids to the esophagus while keeping such material out of the respiratory tract. Keep in mind that the pathway of airflow into the trachea and the pathway for food entering the esophagus intersect within the pharynx. The first step in swallowing is voluntary: the animal uses motor neurons to push the bolus of food to the back of the tongue. Pharyngeal receptors sense the presence of the bolus and afferent fibers of cranial nerves V, IX and X carry this information to the medulla. From this point on, the swallowing reflex is involuntary.

Myoepithelialcells

Acinar cells

Proteinmucus

Intercalatedduct cells

Striated duct cells

Alkaline solution

Acinus

Figure 42.2 Photomicrograph of a salivary gland. Acinar cells produce proteins and antibacterial peptides. Secretion is stimulated by parasympathetic fibers that enhance metabolic activity of acinar cells and also stimulate contraction of myoepithelial cells to expel fluid into ducts. The ducts add an alkaline secretion to the saliva in response to the hormone secretin synthesized in the duodenum.

1 The pathway for food and air cross each other. Describe the steps taken to insure that food does not enter the trachea or the nasopharynx.

K+ Na+ Cl-‐

Secreción pancreá%ca

Basal pH 7,8

Es%mulada (secre%na) pH 8,2

pH Duodeno SEE

Acinos Células mioepiteliales

Células de los conductos estriados Células de conductos Intercalares

Enzimas Mucus

HCO3-‐

Secreción de HCO3-‐ Na+ y K+ y reabsorción de Cl-‐ por las

células de los conductos del páncreas

Células del c

onducto

Células del conducto

Unión estrecha

of the cell, responding to temperature, touch, sound, osmolarity, pH, and various chemical messengers (Holzer, 2007). Among TRP channels, it is known that TRP vanilloid subtypes 1 and 4 (TRPV1 and TRPV4) can respond to acidosis (Clapham, 2003). However, it is unlikely that TRPV1 or 4 are involved in physiological acid sensing, since they are activated only if the extracellular pH is reduced to values below 6 (Holzer, 2004, 2007), which probably happens only under pathophysiological conditions (Behrendorff et al., 2010). The KCNK family members are blocked by very small increases in the extracellular concentration of H+ (Holzer, 2004); therefore, most probably they also do not play a significant role in physiological regulation of the ductal bicarbonate secretion. The ligand-gated P2X are assembled as homo- and heteromultimers of different subunits (P2X1–P2X7; Dunn et al., 2001). The activi-ties of most P2X subunits are modulated by alterations of extra-cellular pH (Holzer, 2003). Although the potency of ATP to gate homomultimeric P2X1, P2X3, P2X4, P2X5, and P2X7 receptors is reduced by mild acidification, homomultimeric P2X2 receptors are sensitized to ATP (Dunn et al., 2001; North, 2002; Holzer, 2003). Since only P2X2 homomultimers and heteromultimers involving P2X2 (P2X1/2, P2X2/3, and P2X2/6) are sensitized by acid, it is primarily P2X2-containing purinoceptors that can function as indirect acid sensors in the presence of ATP (Holzer, 2003). The most likely candidate in pancreatic ductal acid sensing could be ASIC. This channel type was shown to be present in

the HT29 intestinal epithelial cell line (Dong et al., 2011). This type of ion channel has six different subunits, but only five of them are sensitive to protons. The pH sensitivity of each sub-type is different, but subtypes 1a and 3 can be stimulated once extracellular pH drops below 7 (Holzer, 2007), which can easily be reached during physiological enzyme secretion (Behrendorff et al., 2010). ASICs are primarily Na+ channels, but the 1a subunit also allows for the passage of Ca2+. Activation of ASIC usually elevates the cytosolic Ca2+ concentration which in turn can lead to bicarbonate secretion by pancreatic ductal cells (Dong et al., 2011). It is almost needless to say that the characterization of the ductal acid sensing mechanisms is crucially important to understanding the acinar-ductal cooperation in the pancreas.

THE IMPORTANCE OF EXTRACELLULAR pH IN PANCREATITISBoth clinical and experimental observations suggest that acido-sis may increase the risk of developing acute pancreatitis. The incidence of pancreatitis in patients with diabetic ketoacidosis is about 11% (Nair et al., 2000). In organic acidemias, some drugs and mitochondrial tRNA mutations are associated with mito-chondrial dysfunction that cause lactic acidosis and are also linked to acute pancreatitis (Kishnani et al., 1996; Patel and Hedayati, 2006). Besides the clinical observations, experimental models also suggested the harmful effect of acidosis in pancreatitis. Reber et al. (1992) found that in cat pancreas, the basal parenchymal pH was

FIGURE 1 | Changes of luminal pH in the exocrine pancreas during secretion. Under physiological conditions acinar cells secrete digestive enzymes and protons, the latter of which acidify the acinar lumen. In contrast, ductal cells secrete bicarbonate which will elevate the intraluminal pH. Our hypothesis is that protons may stimulate the ductal bicarbonate secretion via acid sensing receptors (ASR), which can elevate the pH in the ductal lumen setting the luminal pH to 8.0. (N, nucleus).

Hegyi et al. Challenge of the acinar acid load

Frontiers in Physiology | Gastrointestinal Sciences July 2011 | Volume 2 | Article 36 | 2

Procarboxipep%dasa A y B

Proelastasa

Quimotripsinógeno

Tripsinógeno

Amilasa (uniones glucosídicas alfa 1-‐4)

Carbohidratos

Proteinas

Lípidos Lipasa (ac%va) Pro-‐colipasa

CCK

+

Pro-‐fosfolipsa

16

9.- Los intestinos… El siguiente esquema muestra aspectos generales de los intestinos, desde el duodeno al recto. a.- Indica las diferencias entre: duodeno, yeyuno-íleon y colon representadas en el esquema.

b.- A continuación se presenta un esquema simplificado de los elementos que estructuran las paredes de los intestinos. A la izquierda, el sistema vascular con: 1.- ramas arteriales y capilares (en negro), 2.- ramas venosas (rayadas); al centro, el sistema linfático con: 4.- vaso quilífero central en la lámina propia (o corion) de la vellosidad (3), 5.- red linfática perifolicular de la lámina propia; luego, el sistema nervioso con: 6.- acúmulos neuronales del plexo de Meissner, 7.- neuronas del plexo mientérico de Auerbach y la distribución de sus prolongaciones; a la derecha, el sistema muscular, con: 8.- musculatura de la vellosidad, 9.- muscular de la mucosa que separa a la lámina propia de la submucosa (10), 11.- capas de musculatura circular interna y 12.- longitudinal externa.

16

9.- Los intestinos… El siguiente esquema muestra aspectos generales de los intestinos, desde el duodeno al recto. a.- Indica las diferencias entre: duodeno, yeyuno-íleon y colon representadas en el esquema.

b.- A continuación se presenta un esquema simplificado de los elementos que estructuran las paredes de los intestinos. A la izquierda, el sistema vascular con: 1.- ramas arteriales y capilares (en negro), 2.- ramas venosas (rayadas); al centro, el sistema linfático con: 4.- vaso quilífero central en la lámina propia (o corion) de la vellosidad (3), 5.- red linfática perifolicular de la lámina propia; luego, el sistema nervioso con: 6.- acúmulos neuronales del plexo de Meissner, 7.- neuronas del plexo mientérico de Auerbach y la distribución de sus prolongaciones; a la derecha, el sistema muscular, con: 8.- musculatura de la vellosidad, 9.- muscular de la mucosa que separa a la lámina propia de la submucosa (10), 11.- capas de musculatura circular interna y 12.- longitudinal externa.

Estructura de la pared

Intes%no Delgado

Submucosa del duodeno proximal: Glándulas de Brunner

Chapter 43: Secretory Activities of the Gastrointestinal Tract 493

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in the lamina propria. A thin smooth muscle, the muscularis mucosae, also extends up into the villi and can be used to shorten and lengthen each villus during the digestive process.

Below the mucosa lies the submucosa. Neurons comprising the submucosal nerve plexus of the enteric nervous system can be found in the submucosa of all regions of the gastrointestinal tract. In the upper duodenum, the submucosa contains many

glands known as Brunner’s glands. These are typical compound tubular glands with acinar structures with a duct system that conveys their secretions ot the base of the crypts. The acinar cells secrete mucus and the duct cells add sodium and potassium to, and remove chloride from, the secretions to form an alkaline secretion. This alkaline fluid is used to flush the crypts and then the villi with this acid‐neutralizing fluid. Secretion by the Brunner’s glands is controlled by the hormone secretin, released by enteroendocrine cells within the crypts of the duodenum when the pH of the fluid in the crypts falls too low. The submu-cosa of the lower duodenum and jejunum are not remarkable. However, the submucosa of the ileum contains unique aggre-gates of B and T lymphocytes, macrophages and dendritic cells known as Peyer’s patches. They occupy large sections of the submucosa and can also extend into the mucosa of the ileum. Peyer’s patches are an important component of the mucosa‐associated lymphoid tissue (MALT) and provide immune sur-veillance of the intestinal lumen, facilitating the generation of immune responses within the mucosa.

The tunica muscularis is below the submucosa and com-prises the inner circular and outer longitudinal smooth muscle layers. The nerve cell bodies of the neurons comprising the myenteric nerve plexus of the enteric nervous system reside between the two muscle layers. Outside this layer is the tunica serosa, a single cell layer of squamous epithelium on a loose connective tissue or adventitia.

Cells within the small intestine cryptsSix cell types exist within the crypts.

Crypt stem cellsThe base of the crypts contain a pluripotent stem cell population that persists throughout the life of the animal. These cells undergo regular division and give rise to the majority of the cells in the crypt. Crypt secretory cells, mucus‐secreting goblet cells, enteroendocrine cells, and Paneth cells all arise from these stem cells. The stem cells do not migrate from the base of the crypts.

Crypt enterocytesThe majority of cells lining the crypts are crypt enterocytes. These cells have microvilli at their apical surface that increase their surface area tremendously. Their primary function is to secrete chloride, sodium and water into the lumen of the crypt to facilitate absorption by absorptive enterocytes in the villus. The crypt enterocytes migrate up the basal lamina toward the villus and eventually up onto the villus itself. Once on the villus, the crypt cells stop being secretory cells and their phenotype switches to that of an absorptive enterocyte. The crypt cells migrate up the lamina propria propelled by means of lamellipo-dia, small actin monomers extending from the basaolateral membrane that interact with integrin proteins on the basal lamina. This allows them to “walk” up the crypts and onto the villus. The crypt cell requires 1–2 days to migrate up the crypt

Figure 43.12 Photomicrograph of microvilli extending from a small intestine epithelial cell. The cord‐like structures extending downward from the microvilli are contractile actin filaments. From Fawcett, D.W. (1986) Bloom and Fawcett: A Textbook of Histology, 11th edn. W.B. Saunders, Philadelphia. Courtesy of N. Hirokawa and J. Heuser. With permission from Elsevier.

Villi Villuscrosssect.

Lpcore

Opening ofcrypt

Laminapropria

Crypts Cross sect.Muscularismucosa

Surface

Figure 43.11 Three‐dimensional representation of the small intestine lining. The villi are finger‐like processes with cores of lamina propria that extend into the lumen. The crypts of Lieberkühn are depressions in the lamina propria (Lp). From Ham, A.W. (1974) Histology, 7th edn. J.B. Lippincott, Philadelphia. Reproduced with permission from Lippincott Williams & Wilkins.


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in the lamina propria. A thin smooth muscle, the muscularis mucosae, also extends up into the villi and can be used to shorten and lengthen each villus during the digestive process.

Below the mucosa lies the submucosa. Neurons comprising the submucosal nerve plexus of the enteric nervous system can be found in the submucosa of all regions of the gastrointestinal tract. In the upper duodenum, the submucosa contains many

glands known as Brunner’s glands. These are typical compound tubular glands with acinar structures with a duct system that conveys their secretions ot the base of the crypts. The acinar cells secrete mucus and the duct cells add sodium and potassium to, and remove chloride from, the secretions to form an alkaline secretion. This alkaline fluid is used to flush the crypts and then the villi with this acid‐neutralizing fluid. Secretion by the Brunner’s glands is controlled by the hormone secretin, released by enteroendocrine cells within the crypts of the duodenum when the pH of the fluid in the crypts falls too low. The submu-cosa of the lower duodenum and jejunum are not remarkable. However, the submucosa of the ileum contains unique aggre-gates of B and T lymphocytes, macrophages and dendritic cells known as Peyer’s patches. They occupy large sections of the submucosa and can also extend into the mucosa of the ileum. Peyer’s patches are an important component of the mucosa‐associated lymphoid tissue (MALT) and provide immune sur-veillance of the intestinal lumen, facilitating the generation of immune responses within the mucosa.

The tunica muscularis is below the submucosa and com-prises the inner circular and outer longitudinal smooth muscle layers. The nerve cell bodies of the neurons comprising the myenteric nerve plexus of the enteric nervous system reside between the two muscle layers. Outside this layer is the tunica serosa, a single cell layer of squamous epithelium on a loose connective tissue or adventitia.

Cells within the small intestine cryptsSix cell types exist within the crypts.

Crypt stem cellsThe base of the crypts contain a pluripotent stem cell population that persists throughout the life of the animal. These cells undergo regular division and give rise to the majority of the cells in the crypt. Crypt secretory cells, mucus‐secreting goblet cells, enteroendocrine cells, and Paneth cells all arise from these stem cells. The stem cells do not migrate from the base of the crypts.

Crypt enterocytesThe majority of cells lining the crypts are crypt enterocytes. These cells have microvilli at their apical surface that increase their surface area tremendously. Their primary function is to secrete chloride, sodium and water into the lumen of the crypt to facilitate absorption by absorptive enterocytes in the villus. The crypt enterocytes migrate up the basal lamina toward the villus and eventually up onto the villus itself. Once on the villus, the crypt cells stop being secretory cells and their phenotype switches to that of an absorptive enterocyte. The crypt cells migrate up the lamina propria propelled by means of lamellipo-dia, small actin monomers extending from the basaolateral membrane that interact with integrin proteins on the basal lamina. This allows them to “walk” up the crypts and onto the villus. The crypt cell requires 1–2 days to migrate up the crypt

Figure 43.12 Photomicrograph of microvilli extending from a small intestine epithelial cell. The cord‐like structures extending downward from the microvilli are contractile actin filaments. From Fawcett, D.W. (1986) Bloom and Fawcett: A Textbook of Histology, 11th edn. W.B. Saunders, Philadelphia. Courtesy of N. Hirokawa and J. Heuser. With permission from Elsevier.

Villi Villuscrosssect.

Lpcore

Opening ofcrypt

Laminapropria

Crypts Cross sect.Muscularismucosa

Surface

Figure 43.11 Three‐dimensional representation of the small intestine lining. The villi are finger‐like processes with cores of lamina propria that extend into the lumen. The crypts of Lieberkühn are depressions in the lamina propria (Lp). From Ham, A.W. (1974) Histology, 7th edn. J.B. Lippincott, Philadelphia. Reproduced with permission from Lippincott Williams & Wilkins.

Estructura de la mucosa (vellosidades y microvellosidades) Intes%no delgado

Microvellosidades de la membrana apical de los enterocitos

Criptas Lámina propia

Muscular de la mucosa

Vellosidades Apertura de la cripta Sección de

una vellosidad

Sección de una cripta

Superficie

Glándulas de Brunner (submucosa duodeno proximal)

Acinos Células de los conductos

Na+ K+ Cl-‐

Mucus

Enterocito de la cripta (secreción) 18

d.- Observa el siguiente esquema que representa un grupo de células del revestimiento epitelial del duodeno:

d.1- Coloca los nombres correspondientes a las estructuras señaladas por las letras A-B-C-D. d.2- Las letras B y C marcan dos tipos de medios de unión. Menciona de cuáles se trata. d.3- La letra E representa una célula secretora, típica del epitelio intestinal: ¿A qué célula se refiere el esquema?. Coloca los nombres señalados con E 1 y E 2. Teniendo en cuenta que esta célula segrega mucoproteína ¿Cómo crees que se la verá al microscopio óptico con la técnica de H/E? ¿Por qué?. e.- Describe el esquema de la mucosa, las vellosidades, las criptas de Lieberkühn y las células que componen el intestino delgado.

A

B

C

D

E

E 1

E 2

18

d.- Observa el siguiente esquema que representa un grupo de células del revestimiento epitelial del duodeno:

d.1- Coloca los nombres correspondientes a las estructuras señaladas por las letras A-B-C-D. d.2- Las letras B y C marcan dos tipos de medios de unión. Menciona de cuáles se trata. d.3- La letra E representa una célula secretora, típica del epitelio intestinal: ¿A qué célula se refiere el esquema?. Coloca los nombres señalados con E 1 y E 2. Teniendo en cuenta que esta célula segrega mucoproteína ¿Cómo crees que se la verá al microscopio óptico con la técnica de H/E? ¿Por qué?. e.- Describe el esquema de la mucosa, las vellosidades, las criptas de Lieberkühn y las células que componen el intestino delgado.

A

B

C

D

E

E 1

E 2

Enterocito de la vellosidad (diges%ón y absorción)

Célula de Paneth

Célula regenera%va

Célula enterocromaYn (SEE)

Célula caliciforme

Tipos Celulares

Intes%no delgado


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quickly. The new cells are unlikely to be fully functional as it takes several days for brush border enzymes to be elaborated. It may take weeks for the villus to recover its full length.

Blood flow within the lamina propria of the villusAn arteriole carries blood to the tip of the villus and this arte-riole is in close proximity to a venule carrying blood away from the capillary beds at the tip of the villus (Figure 43.14). The arte-riole is carrying oxygenated blood that has a Po2 of about 90 mmHg. The venule will have a Po2 of about 40 mmHg. The arteriole and the venule are in such close proximity that a coun-tercurrent process develops. Oxygen diffuses from the arteriole as it ascends the villous tip and the venule picks up this oxygen as it moves blood away from the villous tip. The net result is that the Po2 in the arteriole decreases to about 75 mmHg by the time it reaches the villous tip. The villous tip cells have a huge role in absorption of nutrients and electrolytes and conduct this work in a relatively oxygen‐poor environment. An interesting out-come of this situation is that whenever there is a problem with oxygenation of the blood due to pneumonia or heart disease, the villous tip cells receive even less oxygen and can die and slough off faster. Ischemia or disruption of blood flow to a section of intestine will also result in death of the villous tip cells first. The denuded villus can then allow bacterial invasion through the exposed basal lamina.

Crypt enterocyte secretion of chloride, sodium, and water

While the enterocytes are in the crypts their main function is to secrete chloride, sodium, and water into the lumen of the crypts. This serves two critical functions. The sodium excreted into the lumen of the crypts provides the electrochemical force needed to allow absorption of amino acids, sugars, phosphate, and other nutrients by the villous absorptive cells (described in detail in Chapter 44). There is generally not enough sodium in the diet to perform this critical function, so the crypt cells provide the sodium that allows the villous cells to perform many of their absorptive functions. The water secreted into the lumen by the crypt cells acts to reduce the osmolarity of the digesta, as well as ensuring the digesta remains sufficiently moist to solubilize ions, sugars, and amino acids. Understanding how the crypt enterocytes secrete these ions and water and how this process is controlled will allow the veterinary practitioner to understand the etiology of the “secretory” components of diarrhea.

During digestion within the small intestine, particularly in the duodenum and jejunum, vagal and enteric nervous system sensory afferent neurons sense changes within the lumen such as increased osmolarity, stretch, presence of amino acids in the lumen, or reduced pH and the medulla initiates vagal parasympathetic efferent stimulation of the crypt cells (Figure 43.15). Vagal postganglionic parasympathetic neurons release acetylcholine (ACh) that interacts with muscarinic

Glucose

O2

O2

Figure 43.14 A functional schematic of the blood supply to the small intestinal villus. A central arteriole emerging from the submucosal artery carries oxygenated blood upward toward the villous tip, where a capillary network ramifies outward and is collected into venules and veins, which progress downward at the periphery just beneath the mucosal epithelium. An exchange of oxygen and nutrients can occur in such a hairpin countercurrent arrangement. From Reece, W.O. (2004) Dukes’ Physiology of Domestic Animals, 12th edn. Cornell University Press, Ithaca, NY. Reproduced with permission from Cornell University Press.

Sloughed cells:1000/day

3000 cells tocover eachvillus

300 cellsline eachcrypt

Crypt

A

B

C

Figure 43.13 Several crypts will contribute the cells needed to cover the villus. Shortly after leaving the crypt zone the migrating crypt enterocytes, which were primarily secretory cells, change their phenotype to become villous absorptive cells. It takes 4–5 days for a crypt cell to reach the villous tip. Once there, they last only a period of hours before they are sloughed off into the lumen of the intestine. The crypts contain rapidly dividing stem cells (B), which multiply and differentiate to give rise to secretory crypt enterocytes and goblet cells (A). At the base of the crypts reside enteroendocrine and Paneth cells that were derived from crypt stem cells (C). They do not migrate up to the villi.


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quickly. The new cells are unlikely to be fully functional as it takes several days for brush border enzymes to be elaborated. It may take weeks for the villus to recover its full length.

Blood flow within the lamina propria of the villusAn arteriole carries blood to the tip of the villus and this arte-riole is in close proximity to a venule carrying blood away from the capillary beds at the tip of the villus (Figure 43.14). The arte-riole is carrying oxygenated blood that has a Po2 of about 90 mmHg. The venule will have a Po2 of about 40 mmHg. The arteriole and the venule are in such close proximity that a coun-tercurrent process develops. Oxygen diffuses from the arteriole as it ascends the villous tip and the venule picks up this oxygen as it moves blood away from the villous tip. The net result is that the Po2 in the arteriole decreases to about 75 mmHg by the time it reaches the villous tip. The villous tip cells have a huge role in absorption of nutrients and electrolytes and conduct this work in a relatively oxygen‐poor environment. An interesting out-come of this situation is that whenever there is a problem with oxygenation of the blood due to pneumonia or heart disease, the villous tip cells receive even less oxygen and can die and slough off faster. Ischemia or disruption of blood flow to a section of intestine will also result in death of the villous tip cells first. The denuded villus can then allow bacterial invasion through the exposed basal lamina.

Crypt enterocyte secretion of chloride, sodium, and water

While the enterocytes are in the crypts their main function is to secrete chloride, sodium, and water into the lumen of the crypts. This serves two critical functions. The sodium excreted into the lumen of the crypts provides the electrochemical force needed to allow absorption of amino acids, sugars, phosphate, and other nutrients by the villous absorptive cells (described in detail in Chapter 44). There is generally not enough sodium in the diet to perform this critical function, so the crypt cells provide the sodium that allows the villous cells to perform many of their absorptive functions. The water secreted into the lumen by the crypt cells acts to reduce the osmolarity of the digesta, as well as ensuring the digesta remains sufficiently moist to solubilize ions, sugars, and amino acids. Understanding how the crypt enterocytes secrete these ions and water and how this process is controlled will allow the veterinary practitioner to understand the etiology of the “secretory” components of diarrhea.

During digestion within the small intestine, particularly in the duodenum and jejunum, vagal and enteric nervous system sensory afferent neurons sense changes within the lumen such as increased osmolarity, stretch, presence of amino acids in the lumen, or reduced pH and the medulla initiates vagal parasympathetic efferent stimulation of the crypt cells (Figure 43.15). Vagal postganglionic parasympathetic neurons release acetylcholine (ACh) that interacts with muscarinic

Glucose

O2

O2

Figure 43.14 A functional schematic of the blood supply to the small intestinal villus. A central arteriole emerging from the submucosal artery carries oxygenated blood upward toward the villous tip, where a capillary network ramifies outward and is collected into venules and veins, which progress downward at the periphery just beneath the mucosal epithelium. An exchange of oxygen and nutrients can occur in such a hairpin countercurrent arrangement. From Reece, W.O. (2004) Dukes’ Physiology of Domestic Animals, 12th edn. Cornell University Press, Ithaca, NY. Reproduced with permission from Cornell University Press.

Sloughed cells:1000/day

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Crypt

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Figure 43.13 Several crypts will contribute the cells needed to cover the villus. Shortly after leaving the crypt zone the migrating crypt enterocytes, which were primarily secretory cells, change their phenotype to become villous absorptive cells. It takes 4–5 days for a crypt cell to reach the villous tip. Once there, they last only a period of hours before they are sloughed off into the lumen of the intestine. The crypts contain rapidly dividing stem cells (B), which multiply and differentiate to give rise to secretory crypt enterocytes and goblet cells (A). At the base of the crypts reside enteroendocrine and Paneth cells that were derived from crypt stem cells (C). They do not migrate up to the villi.

1-‐2 días

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B)  Células regeneraMvas C)  Paneth y SEE

300 células recubren la cripta

3000 células recubren la vellosidad

1000-‐1500 células descamadas por día

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receptors on the basolateral membrane of the crypt cells. These receptors are G protein‐coupled receptors linked to phospho-lipase A, so on activation the intracellular concentration of inositol trisphosphate (IP3) rises. IP3 acts on the membrane of internal cell organelles that store calcium, such as the endoplasmic reticulum, and causes calcium channels to open in the the membrane. This releases Ca2+ to the cytosol of the cell where it becomes bound to calmodulin, an important cell regulatory protein, and causes it to become activated. The Ca2+–calmodulin complex then interacts with a Cl– channel pump protein at the apical membrane and causes it to open. It also causes an ATP to donate the energy of a phosphate bond to supply the energy needed to transport the chloride from the inside of the cell, which has a relatively low Cl– concentration (<30 mmol/L), to the lumen of the crypt where Cl– concentration

is substantially higher. This Cl– channel pump is also known as the cystic fibrosis transmembrane conductance regulator pro-tein. The Cl– pumped into the lumen is rapidly replaced by entry of a chloride into the cell from the extracellular fluid ([Cl–] ~105 mmol/L) across the basolateral membrane, alone or cotransported with Na+ or K+. Once chloride has been secreted into the lumen, the negative charges of the Cl– ions in the lumen of the crypt, together with the high Na+ concentration in the extracellular fluid, cause Na+ ions to move from the extracellular fluid to the lumen across the tight cell junctions separating adja-cent crypt enterocytes. Water then follows the solute into the lumen using water channels in the tight cell junctions. In this way, the secretory activity of the crypt cells is coordinated to occur only at the time the villous cells need sodium ions to accomplish absorptive activities.

ACh

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Muscarinic R

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ER

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Na+

Na+

Na+

H2O

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H2O

H2O

H2O Cl–

Cl–

Cl– Cl–

Cl–

Cl–

ACh

Figure 43.15 Crypt secretion of chloride, sodium, and water is normally controlled by vagus parasympathetic innervation. (A) The vagus responds to stretch or osmotic changes in the intestine and releases acetylcholine (ACh). The G protein‐coupled muscarinic receptor resides in the basolateral cell membrane. (B) Activation of muscarinic receptor stimulates G‐protein activation of phospholipase A (PL‐A), which catalyzes production of inositol trisphosphate (IP3). (C) The IP3 moves to the endoplasmic reticulum (ER) and binds to an IP3 receptor causing a Ca2+ channel to open in the ER membrane. (D) Ca2+ binds to calmodulin and the Ca2+–calmodulin complex activates the chloride channel to become active. Cl– is actively pumped out of the cell into the lumen at the expense of ATP. Sodium follows through the tight junction between cells to maintain electroneutrality. Water will also cross the tight junction, pulled by the osmotic gradient created by Cl– and Na+ in the lumen.

Secreción de Cl-‐, Na+ y H2O por las células de las criptas del intes%no delgado


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Crypt cell secretion as a response to inflammation or pathogens

Certain toxins, pathogens, and poisons can cause damage to cells in an area of the intestine. The damaged tissues respond by producing and secreting prostaglandins, primarily PGE2 and PGI2. The prostaglandins diffuse through the lamina propria to reach crypt cells. Crypt enterocytes possess receptors for prosta-glandin on their basolateral membrane. These are G protein‐coupled receptors link to phospholipase A (Figure 43.16). When prostaglandin binds to its receptor, it causes intracellular con-centrations of IP3 to increase in the cytosol of the crypt entero-cyte. This causes Ca2+ channels on the endoplasmic reticulum to open and Ca2+ floods the cytosol. Ca2+–calmodulin complexes form and interact with the apical membrane chloride pump and Cl– is actively pumped out of the cell into the lumen. Extracellular fluid Na+ and water move across the tight junction to follow the Cl– out into the lumen. This action brings large volumes of fluid into the crypt and to surrounding villi to flush the offending toxin away from the area.

Inflammation in a segment of the intestine can also activate crypt secretion activity, presumably to help flush a pathogenic substance away from an area of inflammation. For example, lymphocytes that have become activated by the presence of some “pathogen‐associated molecular pattern” can respond by producing a variety of cytokines. Cytokines such as tumor necrosis factor (TNF)‐α, interleukins, and interferons bind to their respective receptors at the base of the crypt cells and acti-vate adenylyl cyclase or guanylate cyclase. The resulting cyclic AMP or cyclic GMP causes Ca2+ ions to leave intracellular stores and bind to calmodulin. This complex then causes the chloride channel pump to be activated, driving Cl– into the lumen with Na+ and water following through the tight junctions. A slightly different way of stimulating crypt chloride secretion is provided by the action of serotonin (Figure 43.17). Serotonin can be released from enteroendocrine cells in the crypt by the presence of toxins or bacterial cell walls in the lumen of the crypt. The released serotonin diffuses through the lamina propria to

activate nearby crypt cells in a paracrine fashion. Serotonin binds to its receptor, which is linked to a Ca2+ channel in the basolateral cell membrane. The Ca2+ channel opens and extra-cellular Ca2+ floods the cytosol. Again, the Ca2+–calmodulin complex forms and binds to the chloride channel pump, acti-vating secretion of Cl– into the lumen and extracellular Na+ and water cross the tight junction to follow the Cl– into the lumen.

Receptors for all the factors discussed (prostaglandins, cyto-kines, and serotonin associated with cell damage and inflamma-tion) can also be found on goblet cells in the crypts and villi. They respond to these substances by markedly increasing mucus secretion, thought to be a response for flushing away the offend-ing material and coating it with mucus so it will not be as likely to reach the mucosal cells.

Secretory diarrhea caused by bacterial enterotoxinsThe crypt cell secretion activities described so far have been localized to small areas of the intestine that might require Na+ for absorption of sugars and amino acids (described in Chapter 44) or which might use the secretions to flush away pathogens. However, certain bacteria produce toxins that can hijack the normal crypt cell secretion process and cause wide-spread uncontrolled activation of crypt cell secretion. The clas-sic example of this is cholera toxin produced by Vibrio cholerae ingested with contaminated water. The bacteria produce a toxin that is released into the lumen of the small intestine. The cholera toxin binds to proteins (receptors?) at the apical membrane of the crypt enterocyte (Figure 43.18). It is not known why these receptors for cholera toxin exist – it seems logical that there is some natural compound found in the lumen they recognize but none have been identified. Once cholera toxin binds this apical membrane protein, it stimulates activation of guanylate cyclase. Cyclic GMP levels rise inside the cell, causing the Ca2+ channels on the endoplasmic reticulum to open and Ca2+ ions flood the cytosol. This permits Ca2+–calmodulin complexes to form and activate the chloride channel pump. Cl– is secreted into the

PGE2


Prostaglandinreceptor

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PGE2Cl–

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Ca2+

Na+

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Na+ER

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Ca2+ Calmodulin

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Figure 43.16 (A) Prostaglandin E (PGE2), produced in response to damage or reactive oxygen species in the area around the crypt cell, binds to a G protein‐coupled PGE2 receptor. This results in activation of phospholipase A (PL‐A) and production of inositol trisphosphate (IP3). The IP3 causes opening of Ca+2 channels in the endoplasmic reticulum (ER) resulting in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. This same mechanism can be used by tumor necrosis factors, interleukins, and other cytokines to initiate secretory activity that might help flush away harmful compounds or bacteria. This same mechanism works in goblet cells to stimulate mucus secretion.

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lumen and Na+ and water follow. These toxins spread throughout the intestinal tract and activate huge numbers of crypt cells for a prolonged period. To make matters worse, the toxin can also bind to cholera toxin “receptors” on the villous absorptive enterocytes. Again this causes cyclic GMP production and a rise in intracellular Ca2+ and formation of Ca2+–calmodulin complexes. However, in this instance the Ca2+–calmodulin com-plex binds to the Na+/Cl– cotransporter used to absorb lumen Na+ and Cl– across the apical membrane of the villous cells. Shutting down this mechanism for absorption of Na+ and Cl– also reduces the amount of water that can be absorbed. The end result is that crypts are in a state of tremendous hypersecretion and the villous cells have a reduced capacity to absorb, causing a massive loss of fluids and electrolytes with the feces.

In veterinary medicine, the offending bacteria producing entertoxins are likely to be certain strains of Escherichia coli. At least two enterotoxins have been described. One is heat stable (ST toxin) and when it binds to receptors on the apical mem-brane of crypt cells (and villous cells) it activates cyclic GMP production just like cholera toxin, causing a similar severe watery diarrhea. The other enterotoxin produced by a different strain of E. coli is a heat‐labile toxin (LT). This toxin binds to its receptor on the apical surface of enterocytes (crypt and vil-lus) and activates adenylyl cyclase, causing intracellular cyclic AMP levels to rise, triggering increased secretion of Cl– by crypt enterocytes and decreased absorption of Na+ and Cl– by villous enterocytes (Figure 43.19). A notable difference is that when the LT toxin binds to the receptor protein that recognizes

Cl–

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EnteroendocrinecellCa2+

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Release Serotoninto have paracrineaction



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Figure 43.17 (A) An enteroendocrine cell that secretes serotonin when activated neighbors a crypt cell. (B) A bacterial toxin activates receptors at the apical membrane of the enteroendocrine cell causing serotonin vesicles to fuse with the basolateral membrane and secrete serotonin into the lamia propria, where it diffuses toward a serotonin receptor (SR) in the basolateral membrane of the crypt cell. (C) Binding of serotonin causes a conformational change in the receptor allowing it to open Ca2+ channels in the basolateral membrane. Extracellular Ca2+ enters the cell. (D) The rise in cytosolic Ca2+ results in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. Sodium and water follow the chloride into the lumen across the tight junctions.

Acción de toxinas o mucopolisacáridos de paredes bacterianos sobre la secreción de enterocitos

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Figure 43.18 (A) Vibrio cholerae secretes cholera toxin within the lumen of the intestine. A G protein‐coupled receptor that responds to this toxin resides in the apical membrane of the cell. (B) On binding to the receptor, the G protein activates guanylyl cyclase (GC). The GC converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cyclic GMP). (C) The cyclic GMP activates kinases and pathways that cause Ca2+ channels in the endoplasmic reticulum to open. This results in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. Sodium and water follow the chloride into the lumen across the tight junctions.

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Calmodulin

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Choleratoxin

(A)

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Figure 43.19 (A) Certain strains of Escherichia coli secrete enterotoxin (LT toxin) within the lumen of the intestine. A G protein‐coupled receptor responds to this toxin in the apical membrane of the crypt (and villus) cells. (B) On binding to the receptor, the G protein activates adenylyl cyclase (AC). The AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). (C) The cAMP activates kinases and pathways that cause Ca2+ channels in the endoplasmic reticulum to open. This results in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. Sodium and water follow the chloride into the lumen across the tight junctions. In villous cells, the toxin’s action is similar but results in blockade of the Na+/Cl–absorption cotransporter in the apical membrane.

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E. coli secretes LT enterotoxin

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Figure 43.18 (A) Vibrio cholerae secretes cholera toxin within the lumen of the intestine. A G protein‐coupled receptor that responds to this toxin resides in the apical membrane of the cell. (B) On binding to the receptor, the G protein activates guanylyl cyclase (GC). The GC converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cyclic GMP). (C) The cyclic GMP activates kinases and pathways that cause Ca2+ channels in the endoplasmic reticulum to open. This results in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. Sodium and water follow the chloride into the lumen across the tight junctions.

G Protein

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Choleratoxin

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Figure 43.19 (A) Certain strains of Escherichia coli secrete enterotoxin (LT toxin) within the lumen of the intestine. A G protein‐coupled receptor responds to this toxin in the apical membrane of the crypt (and villus) cells. (B) On binding to the receptor, the G protein activates adenylyl cyclase (AC). The AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). (C) The cAMP activates kinases and pathways that cause Ca2+ channels in the endoplasmic reticulum to open. This results in formation of the Ca2+–calmodulin complex and activation of the apical membrane chloride transporter. Sodium and water follow the chloride into the lumen across the tight junctions. In villous cells, the toxin’s action is similar but results in blockade of the Na+/Cl–absorption cotransporter in the apical membrane.

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E. coli secretes LT enterotoxin

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E. Coli Toxina termolábil

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Acción de toxinas o de E.Coli sobre la secreción de enterocitos

19

f.- La mucosa del intestino grueso secreta moco y es la responsable principal de la absorción del agua y los electrólitos de las heces. El contenido intestinal es líquido cuando alcanza el intestino grueso, pero, debido a la reabsorción de agua, se solidifica a medida que alcanza el recto en forma de heces. Las bacterias del intestino grueso también fabrican algunas sustancias importantes, como la vitamina K. Describe el siguiente esquema de la mucosa del colon.

10.- El hígado es la glándula de mayor tamaño del organismo. Es un órgano con diversidad de funciones tales como la detoxificación, el fraccionamiento de nutrientes absorbidos a nivel intestinal y la secreción de bilis.

a.- Explica cómo es la irrigación hepática.

Intes%no grueso y ciego Mucus y HCO3-‐

Descamación luego de 1-‐2 días

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it, it binds irreversibly: the affected cell will hypersecrete Cl– and fail to absorb Na+ and Cl– until it is finally sloughed from the villous tip.

Intestinal epithelial cell secretion of secretory IgAThe intestinal mucosa derives some protection from immuno-globulin secreted into the lumen of the gut. Antibodies can bind toxins and pathogens rendering them less harmful to the animal. Antibodies also facilitate phagocytosis by neutrophils and other cells present in the lumen. Plasma cells within the lamina pro-pria synthesize dimers of immunoglobulin A (IgA). Special pro-teins called secretory piece extend from the basolateral surface of the enterocytes and act as IgA receptors. Once the IgA dimer binds to the secretory piece it stimulates endocytosis of the IgA dimer bound to the secretory piece. The endosome traverses the enterocyte and fuses with the apical membrane. The attachment of the secretory protein to the membrane vesicle is severed and the IgA dimer enters the lumen of the intetine with a piece of the secretory protein attached. The presence of secretory protein on the IgA dimer provides it with resistance to proteolysis by digestive enzymes in the lumen of the intestinal tract.

Large intestine

The cecum and colon are very similar in their microscopic appearance. The mucosa contains crypts (but not villi) lined pri-marily by goblet cells that secrete a slighlty alkaline mucus. There are also some absorptive epithelial cells (Figure 43.20). As in the small intestine, a small population of colon crypt stem cells is found at the base of each crypt. Both the goblet and absorptive epithelial cells migrate toward the top of the crypt. After a short time at the top of the crypt (1–2 days) the cells undergo apo-ptosis and are sloughed off. Under normal circumstances the amount of mucus secreted by the crypts is relatively small but that can change dramatically should infection damage the colon cells and cause release of prostaglandins or inflammatory cyto-kines. The absorptive epithelial cells of the crypts can absorb some electrolytes and the last remnants of water from the ingesta.

Acid–base secretion summary

A 20‐kg dog would be expected to produce about 600 mL of gastric juice with a pH of about 1.2. That same dog will secrete

about 300 mL of saliva, 600 mL of pancreatic juice, 300 mL of bile, and 300 mL from the Brunner’s glands and crypt cell secre-tory efforts. These secretions are slightly alkaline and have a pH of about 8.0. All these secretions are essentially isotonic. It would seem unlikley that 1500 mL of secretions with a pH of 8.0 could neutralize 600 mL of gastric fluid with a pH of 1.5. The gastric juices will also be partially neutralized by components in the diet as well. The chyme leaving the stomach will generally have a pH of 2.0–2.25. A major aid to the increase in pH of duodenal contents is the rapid reabsorption of Cl– ions from the chyme by the upper duodenal villous absorptive enterocytes (described further in Chapter 44).

Self‐evaluation

Answers can be found at the end of the chapter.

1 What kind of cells produce histamine within the gastrointestinal tract?

2 Giving nonsteroidal anti‐inflammatory drugs for long periods can cause ulcers to develop because many NSAIDs block (A) __________, resulting in failure of damaged cells to produce (B) __________. This leads to failure to increase (C) __________ needed for cell repair.

3 The alkalinity of pancreatic fluid is achieved by pancreatic duct cells that resorb (A) __________ ions from the pancreatic acinar secre-tions and add (B) __________ ions to those secretions.

1 Identify the major layers found in the colon.

1 How is it possible to neutralize stomach acid in the upper small intestine?

Colon mucosa

Lymphoid folliclewithinsubmucosa

Inner circular SM

Outer longitudinal SM

Serosa

Figure 43.20 A 10× view of colon tissue from a dog. Lymphoid follicles serve an important role in protecting the body from bacteria and viruses that might be present in the lumen of the colon. Lymphocytes are also common in the lamina propria of the colon mucosa.

Tejido linfoide en la submucosa

Intes%no grueso y ciego

Controla la invasión de la mucosa y submucosa por la microbiota de las cámaras de fermentación

Microbiota

section vii: digestion, absorption, and metabolism · section vii: digestion, absorption, and...

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