Functional ion channels in pulmonary alveolar type I cells support a role for type I cells in lung ion transport

Efficient gas exchange in the lungs depends on regulation of the amount of fluid in the thin (average 0.2 mum) liquid layer lining the alveolar epithelium. Fluid fluxes are regulated by ion transport across the alveolar epithelium, which is composed of alveolar type I (TI) and type II (TII) cells. The accepted paradigm has been that TII cells, which cover <5% of the internal surface area of the lung, transport Na(+) and Cl(-) and that TI cells, which cover >95% of the surface area, provide a route for water absorption. Here we present data that TI cells contain functional epithelial Na(+) channels (ENaC), pimozide-sensitive cation channels, K(+) channels, and the cystic fibrosis transmembrane regulator. TII cells contain ENaC and cystic fibrosis transmembrane regulator, but few pimozide-sensitive cation channels. These findings lead to a revised paradigm of ion and water transport in the lung in which (i) Na(+) and Cl(-) transport occurs across the entire alveolar epithelium (TI and TII cells) rather than only across TII cells; and (ii) by virtue of their very large surface area, TI cells are responsible for the bulk of transepithelial Na(+) transport in the lung.     

Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis

Transport of lung liquid is essential for both normal pulmonary physiologic processes and for resolution of pathologic processes. The large internal surface area of the lung is lined by alveolar epithelial type I (TI) and type II (TII) cells; TI cells line >95% of this surface, TII cells <5%. Fluid transport is regulated by ion transport, with water movement following passively. Current concepts are that TII cells are the main sites of ion transport in the lung. TI cells have been thought to provide only passive barrier, rather than active, functions. Because TI cells line most of the internal surface area of the lung, we hypothesized that TI cells could be important in the regulation of lung liquid homeostasis. We measured both Na(+) and K(+) (Rb(+)) transport in TI cells isolated from adult rat lungs and compared the results to those of concomitant experiments with isolated TII cells. TI cells take up Na(+) in an amiloride-inhibitable fashion, suggesting the presence of Na(+) channels; TI cell Na(+) uptake, per microgram of protein, is approximately 2.5 times that of TII cells. Rb(+) uptake in TI cells was approximately 3 times that in TII cells and was inhibited by 10(-4) M ouabain, the latter observation suggesting that TI cells exhibit Na(+)-, K(+)-ATPase activity. By immunocytochemical methods, TI cells contain all three subunits (alpha, beta, and gamma) of the epithelial sodium channel ENaC and two subunits of Na(+)-, K(+)-ATPase. By Western blot analysis, TI cells contain approximately 3 times the amount of alphaENaC/microg protein of TII cells. Taken together, these studies demonstrate that TI cells not only contain molecular machinery necessary for active ion transport, but also transport ions. These results modify some basic concepts about lung liquid transport, suggesting that TI cells may contribute significantly in maintaining alveolar fluid balance and in resolving airspace edema.     

Na(+)-H(+) exchange in salivary secretory cells is controlled by an intracellular Na(+) receptor.

It recently has been shown that epithelial Na(+) channels are controlled by a receptor for intracellular Na(+), a G protein (G(o)), and a ubiquitin-protein ligase (Nedd4). Furthermore, mutations in the epithelial Na(+) channel that underlie the autosomal dominant form of hypertension known as Liddle's syndrome inhibit feedback control of Na(+) channels by intracellular Na(+). Because all epithelia, including those such as secretory epithelia, which do not express Na(+) channels, need to maintain a stable cytosolic Na(+) concentration ([Na(+)](i)) despite fluctuating rates of transepithelial Na(+) transport, these discoveries raise the question of whether other Na(+) transporting systems in epithelia also may be regulated by this feedback pathway. Here we show in mouse mandibular secretory (endpiece) cells that the Na(+)-H(+) exchanger, NHE1, which provides a major pathway for Na(+) transport in salivary secretory cells, is inhibited by raised [Na(+)](i) acting via a Na(+) receptor and G(o). This inhibition involves ubiquitination, but does not involve the ubiquitin protein ligase, Nedd4. We conclude that control of membrane transport systems by intracellular Na(+) receptors may provide a general mechanism for regulating intracellular Na(+) concentration.     

基于病原体学的急性呼吸道感染住院患儿非细菌性病原学混合感染特点研究

目的 通过回顾性分析本院儿科急性呼吸道感染住院患儿的非细菌性病原学混合感染的特点.方法 研究2014年5月至2015年3月我院儿内科住院治疗的急性呼吸道感染患儿,于入院24 h内取静脉血2 ml应用间接免疫荧光检测9种常见呼吸道病原早期特异性抗体IgM.对所得病原学检测结果及临床资料进行统计分析.结果 患儿中总阳性率51.2％ (147/287);各病原检出率以流感病毒A占首位30.0％ (86/287),其次是流感病毒B为28.2％ (81/287).3～6岁年龄组病原检出率56.3％ (54/96)及病原混合感染率40.6％ (39/96)均最高,其中以流感病毒B合并流感病毒A的双重感染最常见(48.5％;16/33).按月份分布,8月份病原检出率最高,占80.0％ (12/15).根据病原检测结果分组,三组间临床特征发热、咳嗽、病种(上、下呼吸道感染)、住院天数及白细胞计数差异均无统计学意义.流感病毒A、流感病毒B及副流感病毒1在混合感染中阳性率较单一感染高(P＜0.05).结论 本地区儿童急性呼吸道感染病原混合感染率占有一定比例,以流感病毒A检出率占首位,流感病毒B次之.双重感染多见.多发生于3～6岁儿童,8月份为混合感染的发病高峰期.     

Na transport in the cochlea of mammals

Endolymph, the fluid that bathes the apical side of the inner ear sensory cells, is a K-rich and Na-poor fluid. In the cochlea, various epithelial transport systems involved in the transport of Na from the apical endolymphatic to the basolateral perilymphatic compartments have been identified: basolateral Na+, K(+)-ATPase, apical non selective cationic channels, Na+/H+ exchanger, and ENaC epithelial Na channel. These transporters may be involved in physiological and pathological processes in which endolymph Na concentration is high.     

Patterns of alveolar fluid clearance in heart failure

Alveolar fluid clearance (AFC) is important in keeping the airspaces free of edema. This process is accomplished via passive and active transport of Na(+) across the alveolo-capillary barrier mostly by apical Na(+) channels and basolateral Na,K-ATPases, respectively. Patterns of alveolar fluid clearance were found to be decreased in acutely elevated left atrial pressures, possibly due to the inhibition of alveolar epithelial active sodium transport. On the other hand, chronic elevation of pulmonary capillary pressure, such as seen in experimental and clinical congestive heart failure, increases alveolar fluid clearance most likely secondary to upregulation of active sodium transport.     

Oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome?

Levels of oleic acid (OA) are elevated in plasma and bronchoalveolar lavage fluids of patients with acute respiratory distress syndrome (ARDS). OA is also widely used to provoke edema, by unknown mechanisms, in experimental models of ARDS. We investigated the impact of intravascularly applied OA on epithelial lining fluid balance. OA (25 microM) dramatically blocked active transepithelial (22)Na(+) transport (by 92%) in an isolated, ventilated, and perfused rabbit lung model, provoking alveolar edema, assessed by increases in lung weight and epithelial lining fluid volume. OA did not alter epithelial permeability, measured by [(3)H]mannitol and fluorescently labeled albumin flux, but did increase endothelial permeability, assessed by capillary filtration coefficient. In A549 cells, OA completely blocked amiloride-sensitive sodium currents measured by patch clamp, and also largely abrogated ouabain-sensitive Na(+),K(+)-ATPase-mediated (86)Rb(+) uptake. Although OA did not alter epithelial sodium channel or Na(+),K(+)-ATPase surface expression, it covalently associated with both molecules and directly, dramatically, and dose-dependently inhibited the catalytic activity of purified Na(+),K(+)-ATPase. Therefore, OA impaired the two essential transepithelial active sodium transport mechanisms of the lung, and could thus promote alveolar edema formation and prevent edema resolution, thereby contributing to the development of ARDS.     

The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels

Epithelial Na(+) channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, with loss of this inhibition leading to hypertension. Here, we report that these channels are maintained in the active state by the G protein-coupled receptor kinase, Grk2, which has been previously implicated in the development of essential hypertension. We also show that Grk2 phosphorylates the C terminus of the channel beta subunit and renders the channels insensitive to inhibition by Nedd4-2. This mechanism has not been previously reported to regulate epithelial Na(+) channels and provides a potential explanation for the observed association of Grk2 overactivity with hypertension. Here, we report a G protein-coupled receptor kinase regulating a membrane protein other than a receptor and provide a paradigm for understanding how the interaction between membrane proteins and ubiquitin protein ligases is controlled.     

Differential recruitment of dendritic cells and monocytes to respiratory mucosal sites in children with influenza virus or respiratory syncytial virus infection

BACKGROUND: Influenza virus and respiratory syncytial virus (RSV) are among the most common viruses causing infections of the lower respiratory tract in young children. Although there are important differences in the immunopathogenesis of these 2 viral pathogens, little is known about how they affect antigen-presenting cells in children with acute infections. METHODS: To characterize the immune cells that are mobilized to the respiratory tract by influenza virus and RSV, we analyzed nasal wash and blood samples obtained from children hospitalized with acute respiratory infections. RESULTS: Influenza virus and RSV mobilize immune cells, including myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), to the nasal mucosa. Patients with influenza virus infection had greater numbers of mDCs, pDCs, and monocytes in nasal wash samples than did patients with RSV infection. The frequencies of respiratory tract and blood T cell subsets were not affected by infection with influenza virus or RSV. Monocyte chemoattractant protein-1 concentrations in nasal wash samples were significantly increased in patients with influenza virus infection but not in those with RSV infection. RANTES (regulated on activation, normally T cell expressed and secreted) concentrations were increased only in the blood of patients with influenza virus infection. CONCLUSIONS: Infection with influenza virus or RSV mobilizes antigen-presenting cells to the respiratory tract. The differences in antigen-presenting cell numbers and cytokine concentrations suggest that there are distinctive, early immune responses to these 2 viruses.     

From the Cover: Estrogen action and male fertility: Roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function

Estrogen receptor alpha (ER alpha) is essential for male fertility. Its activity is responsible for maintaining epithelial cytoarchitecture in efferent ductules and the reabsorption of fluid for concentrating sperm in the head of the epididymis. These discoveries and others have helped to establish estrogen's bisexual role in reproductive importance. Reported here is the molecular mechanism to explain estrogen's role in fluid reabsorption in the male reproductive tract. It is shown that estrogen regulates expression of the Na(+)/H(+) exchanger-3 (NHE3) and the rate of (22)Na(+) transport, sensitive to an NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII), and aquaporin-I (AQP1) was decreased in ER alpha knockout (alpha ERKO) efferent ductules. Targeted gene-deficient mice were compared with alpha ERKO, and the NHE3 knockout and CAII-deficient mice showed alpha ERKO-like fluid accumulation, but only the NHE3 knockout and alpha ERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in alpha ERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in alpha ERKO seemed to be secondary because of the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in alpha ERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na(+) transport. Finally, these data raise the possibility of targeting ER alpha in developing a contraceptive for the male.     

Amiloride-insensitive nasal potential difference varies with the menstrual cycle in cystic fibrosis

RATIONALE: There is no adequate explanation for gender-based differences in rates of mortality and of deterioration in pulmonary function in cystic fibrosis (CF) patients. One potential explanation is that gender hormones (sex steroids) may modulate the severity of CF lung disease, the principal cause of mortality in CF, by altering respiratory transepithelial ion transport. OBJECTIVE: To determine whether respiratory epithelial ion transport varied during the menstrual cycle of CF females. METHODS: The nasal transepithelial electrical potential difference (NPD) was determined as a measure of ion transport across human respiratory epithelium, coincident with measurements of endogenous serum hormone levels in the luteal and follicular phases of the menstrual cycle in CF females aged 16-22 years. RESULTS: The component of the NPD that is insensitive to the Na(+) transport blocker amiloride, but not the amiloride-sensitive component, changed in association with endogenous, menstrual cycle-induced changes in serum levels of progesterone and estrogen (P=0.02, n=7, paired t-test). Measurements using Cl(-) free perfusates suggested that the changes are not a result of Cl(-) conductance. CONCLUSIONS: Our results suggest that in CF respiratory epithelium amiloride-insensitive, but not amiloride-sensitive, ion transport is altered by female gender hormones in vivo. We speculate that amiloride-insensitive ion transport may contribute to the regulation of human airway surface fluid.     

Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics

Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na(+) absorption, mediated by epithelial Na(+) channels (ENaC), and deficient Cl(-) transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO(3)(-) secretion. In other epithelial tissues, epithelial Na(+) conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl(-) channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl(-) channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways. In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y(2) receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na(+) absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca(2+)-dependent Cl(-) channel is activated that may compensate for the CFTR Cl(-) channel defect. Thus activation of P2Y(2) receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y(2) receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na(+) transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.     

Mechanisms of airway epithelial ion transport

Airway epithelia contain the transport mechanisms required to effect either chloride secretion or sodium absorption. Thus, depending on the local neurohumoral environment, they have the ability to either secrete or absorb fluid. Therefore, they are in a unique position to precisely regulate the quantity and composition of the respiratory tract fluid. The importance of the respiratory tract fluid as a pulmonary defense mechanism is clear. This point is emphasized by the substantial morbidity and mortality that result from abnormalities of airway epithelial function in controlling the quantity and composition of fluid in diseases such as cystic fibrosis and asthma, and in conditions such as cigarette smoking. Therefore, it is essential to understand the function of the epithelium, its regulation, and the mechanism of ion transport at the level of the individual transport processes on the two cell membranes. As our understanding of the mechanism of ion transport increases, we may be able to define a more rational therapy of disease.     

Minireview: regulation of epithelial Na+ channel trafficking

The epithelial Na(+) channel (ENaC) is a pathway for Na(+) transport across epithelia, including the kidney collecting duct, lung, and distal colon. ENaC is critical for Na(+) homeostasis and blood pressure control; defects in ENaC function and regulation are responsible for inherited forms of hypertension and hypotension and may contribute to the pathogenesis of cystic fibrosis and other lung diseases. An emerging theme is that epithelial Na(+) transport is regulated in large part through trafficking mechanisms that control ENaC expression at the cell surface. ENaC trafficking is regulated at multiple steps. Delivery of channels to the cell surface is regulated by aldosterone (and corticosteroids) and vasopressin, which increase ENaC synthesis and exocytosis, respectively. Conversely, endocytosis and degradation is controlled by a sequence located in the C terminus of alpha, beta, and gammaENaC (PPPXYXXL). This sequence functions as an endocytosis motif and as a binding site for Nedd4-2, an E3 ubiquitin protein ligase that targets ENaC for degradation. Mutations that delete or disrupt this motif cause accumulation of channels at the cell surface, resulting in Liddle's syndrome, an inherited form of hypertension. Nedd4-2 is a central convergence point for ENaC regulation by aldosterone and vasopressin; both induce phosphorylation of a common set of three Nedd4-2 residues, which blocks Nedd4-2 binding to ENaC. Thus, aldosterone and vasopressin regulate epithelial Na(+) transport in part by altering ENaC trafficking to and from the cell surface.     

梧州地区住院患者呼吸道病毒及非典型病原体的抗体检测分析

目的探讨梧州地区急性呼吸道感染住院患者呼吸道病毒和非典型病原体感染的情况。方法2014年7月至2015年6月在广西梧州市工人医院住院的急性呼吸道感染患者血清,应用间接免疫荧光法(IFA)定性检测九种呼吸道感染病毒及非典型病原体Ig M抗体,分别是流感病毒A/B、副流感病毒、呼吸道合胞病毒、腺病毒、嗜肺军团菌、肺炎支原体、肺炎衣原体、Q热立克次体。结果呼吸道病原体血清抗体总阳性率为20.97%,其中肺炎支原体阳性率最高,其次B型流感病毒、副流感病,分别是15.80%、2.43%、1.97%。一年中,秋季血清阳性率最高(50.00%),其次冬季(20.13%),与春季、夏季比较差异有统计学意义(P0.05)。不同年龄段中,青年血清阳性率最高,老年组血清阳性率最低。18例B型流感病毒血清阳性中,合并支原体血清阳性9例(9/18=50.00%),12例副流感病毒中,合并支原体7例(7/12=58.33%)。结论 :梧州地区急性呼吸道感染住院患者吸道病毒和非典型呼吸道病原体感染率较高,并以肺炎支原体最高,其次B型流感病毒、副流感病毒;且青年组较老年组发病率高;以秋、冬季节高发;流感病毒、副流感病毒血清阳性混合感染肺炎支原体发生率较高。     

Adenosine regulation of alveolar fluid clearance

Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na(+) transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A(1)R), 2a (A(2a)R), 2b (A(2b)R), and 3 (A(3)R) adenosine receptors are present in rat and mouse lungs and alveolar type 1 and 2 epithelial cells (AT1 and AT2). Rat AT2 cells generated and produced cAMP in response to adenosine, and micromolar concentrations of adenosine were measured in bronchoalveolar lavage fluid from mice. Ussing chamber studies of rat AT2 cells indicated that adenosine affects ion transport through engagement of A(1)R, A(2a)R, and/or A(3)R through a mechanism that increases CFTR and amiloride-sensitive channel function. Intratracheal instillation of low concentrations of adenosine (< or =10(-8)M) or either A(2a)R- or A(3)R-specific agonists increased alveolar fluid clearance (AFC), whereas physiologic concentrations of adenosine (> or =10(-6)M) reduced AFC in mice and rats via an A(1)R-dependent pathway. Instillation of a CFTR inhibitor (CFTR(inh-172)) attenuated adenosine-mediated down-regulation of AFC, suggesting that adenosine causes Cl(-) efflux by means of CFTR. These studies report a role for adenosine in regulation of alveolar ion transport and fluid clearance. These findings suggest that physiologic concentrations of adenosine allow the alveolar epithelium to counterbalance active Na(+) absorption with Cl(-) efflux through engagement of the A(1)R and raise the possibility that adenosine receptor ligands can be used to treat pulmonary edema.     

Prolactin increases Na+ transport across adult bullfrog skin via stimulation of both ENaC and Na+/K+-pump

PRL is involved in osmoregulation in lower vertebrates. Its serum concentration starts to increase during the metamorphosis of bullfrog tadpoles. Adult bullfrog skin transports Na(+) from the apical to the basolateral side across the skin. PRL is involved in the regulation of this transport. We investigated the effect of ovine PRL on the epithelial Na(+) channel (ENaC), Na(+)/K(+)-pump, and basolateral K(+) channels, which regulate Na(+) transport across adult bullfrog skin, by measuring the short-circuit current (SCC). At 0.1 microg/ml, PRL had no effect on the SCC. PRL (1 microg/ml) was sufficient to stimulate the SCC since 1 and 10 microg/ml of PRL each increased SCC 1.8-fold. Current-fluctuation analysis revealed that PRL (10 microg/ml) increased the density of active ENaC almost 1.8-fold. The effect of PRL on the Na(+)/K(+)-pump was investigated using apically nystatin-permeabilized skin with Ca-free Na-Ringers' solution on each side. PRL (10 microg/ml) increased SCC in this condition around 1.1-fold, suggesting that PRL stimulates the Na(+)/K(+)-pump [although PRL (1 microg/ml) had no effect on this SCC]. The effect of PRL on basolateral K(+) channels was investigated using apically nystatin-permeabilized skin with high-K Ringer's solution on the apical side. PRL (10 microg/ml) had no effect on the SCC, suggesting that PRL does not affect basolateral K(+) channels. Thus, although PRL stimulates the Na(+)/K(+)-pump, this effect probably contributes less than that on ENaC to the regulation of Na(+) transport across adult bullfrog skin.     

鸭呼吸道和消化道流感病毒SA受体的分布特征

目的探讨鸭流感病毒受体分布特点及其作用。方法应用凝集素组织化学染色技术检测鸭呼吸道和消化道流感病毒SA受体的分布,用荧光素Alexa488标记禽流感病毒H9N1、人流感病毒H1N1,观察这两种病毒与鸭呼吸道、消化道各解剖部位结合特点。结果SAα-2,3Gal受体在鸭呼吸道气管、支气管、次级支气管、副支气管和消化道结肠呈高密度分布,而SAot-2,6Gal受体缺乏或仅极少量表达。禽流感病毒H9N1能与鸭呼吸道和消化道上皮细胞结合,而人流感病毒H1N1与副支气管和结肠未见结合反应,仅极少量与气管、支气管、次级支气管结合。结论水禽类鸭流感病毒SA受体的分布以SAα-2,3Gal受体为主,在呼吸道和消化道均呈高密度分布,有利于各亚型禽流感病毒在其复制、基因重配。     

Pathogenesis of diarrhea in the adult: diagnostic challenges and life-threatening conditions

The mechanisms that regulate ionic balance, fluid absorption and secretion in the gastrointestinal tract are complex. Disturbance of this homeostatic state by bile acids, bacterial enterotoxins and neoplasm-derived secretagogues, for example, can lead to diarrhea. Determining the causes of chronic diarrhea in individual patients may, therefore, represent a diagnostic challenge. The gastrointestinal tract has finely tuned mechanisms to maintain ionic balance, fluid absorption and secretion. To achieve this homeostasis, various ionic transport proteins/complexes are targeted to the apical, basal or basolateral membranes of epithelial cells. Na, K and Cl ion transport proteins are regulated by endogenous activators (e.g. cAMP, PGE2, Ca), dietary-related factors (e.g. bile acids) and through post-translational modifications (e.g. phosphorylation). In certain pathophysiologic states, this homeostatic ionic/fluid exchange becomes dysfunctional as a result of failure of compensatory pro-absorptive/anti-secretory mechanisms. The excessive secretion of Na and Cl ions followed by the release of a large amount of H2O into the colonic lumen results in diarrhea, which may be acute or chronic, and can be life-threatening if not ameliorated. Diverse infectious organisms (e.g. bacteria, protozoa, viruses) utilize different mechanisms to cause intestinal disease and diarrhea. These pathophysiologic mechanisms include alterations in ion transport, disruption of tight junctions and elicitation of inflammatory responses. Studies of patients infected with certain pathogens, those with ulcerative colitis and those harboring extra-colonic or colonic neoplasms have elucidated some of these pathophysiologic mechanisms of diarrhea. Determining the etiology of chronic diarrhea in specific cases may be a diagnostic challenge for both gastroenterologists and primary care physicians.