Infected epithelial cells also show heightened secretory responses to a variety of cAMP-dependent and other chloride secretagogues, such as galanin, further exacerbating fluid loss. The increases in both basal and stimulated secretion appear to result from the sequential induction of expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In turn, the products of these enzymes not only elevate cyclic nucleotide second messengers that are capable of directly stimulating chloride secretion, but also cause increased expression of CFTR and NKCC1, resulting in a hypersecretory phenotype . Finally, infected cells have impaired barrier function, which also appears to depend on iNOS (but not COX-2) induction . This phenomenon probably further contributes to diarrhea in vivo by rendering the epithelium incapable of sustaining the electrochemical gradients needed for absorptive fluxes. The later effects of Salmonella infection that may account for the diarrheal responses are depicted in Figure 3.
Figure 3) Late (hours to days) signaling events that occur in intestinal epithelial cells infected with Salmonella typhimurium, and their consequences. Following bacterial invasion , signals delivered by the bacteria result in the sequential upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) . Mediators produced by these enzymes (nitric oxide and prostanoids) elevate intracellular cGMP and cAMP, respectively, resulting in stimulation of apical cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels and consequent chloride secretion. Inducible nitric oxide synthase (iNOS) activity also leads to increased, expression of CFTR and the sodium/potassium/2 chloride cotransporter, NKCC1, and their insertion into the membrane , further amplifying the hypersecretory phenotype and possibly contributing to diarrhea . Further details are provided in the text. AP Apical; BL Basolateral
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