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MUCOSAL BIOLOGY

Intracellular Ca²⁺ and Zn²⁺ signals during monochloramine-induced oxidative stress in isolated rat colon crypts

¹Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ²Division of Colon and Rectal Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota

Submitted 8 November 2004 ; accepted in final form 25 May 2005

During acute exacerbations of inflammatory bowel diseases, oxidants are generated through the interactions of bacteria in the lumen, activated granulocytes, and cells of the colon mucosa. In this study we explored the ability of one such class of oxidants, represented by monochloramine (NH₂Cl), to serve as agonists of Ca²⁺ and Zn²⁺ accumulation within the colonocyte. Individual colon crypts prepared from Sprague-Dawley rats were mounted in perfusion chambers after loading with fluorescent reporters fura 2-AM and fluozin 3-AM. These reporters were characterized, in situ, for responsiveness to Ca²⁺ and Zn²⁺ in the cytoplasm. Responses to different concentrations of NH₂Cl (50, 100, and 200 µM) were monitored. Subsequent studies were designed to identify the sources and mechanisms of NH₂Cl-induced increases in Ca²⁺ and Zn²⁺ in the cytoplasm. Exposure to NH₂Cl led to dose-dependent increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in the range of 200–400 nM above baseline levels. Further studies indicated that NH₂Cl-induced accumulation of Ca²⁺ in the cytoplasm is the result of release from intracellular stores and basolateral entry of extracellular Ca²⁺ through store-operated channels. In addition, exposure to NH₂Cl resulted in dose-dependent and sustained increases in intracellular Zn²⁺ concentration ([Zn²⁺]_i) in the nanomolar range. These alterations were neutralized by dithiothreitol, which shields intracellular thiol groups from oxidation. We conclude that Ca²⁺- and Zn²⁺-handling proteins are susceptible to oxidation by chloramines, leading to sustained, but not necessarily toxic, increases in [Ca²⁺]_i and [Zn²⁺]_i. Under certain conditions, NH₂Cl may act not as a toxin but as an agent that activates intracellular signaling pathways.

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