Biomedical subjects

Patricia W Lin

Publications and source records attributed to Patricia W Lin.

3 recordsLinked to original sources

PubMed2006

Necrotising enterocolitis.

Necrotising enterocolitis is one of the most common gastrointestinal emergencies in newborn infants. Here we review the epidemiology, clinical presentation, and pathophysiology of the disease, as well as strategies for diagnosis, management, and prevention. Necrotising enterocolitis is one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, its pathogenesis remains unclear; diagnosis can be difficult; and treatment is challenging. We will need to improve our understanding of intestinal defences in premature infants, dietary and bacterial factors, and genetic effects that could predispose infants to necrotising enterocolitis before we can develop new strategies for prevention and treatment.

Enterocolitis, Necrotizing↗

PubMed2004

Paneth cell cryptdins act in vitro as apical paracrine regulators of the innate inflammatory response.

Intestinal-specific antimicrobial alpha-defensins, termed cryptdins, are secreted into the intestinal lumen by mouse Paneth cells in response to microbial pathogens. Cryptdins kill microbes by forming pores in their limiting membranes. The cryptdin isoforms 2 and 3 also can form anion-conductive pores in eukaryotic cell membranes, thus affecting cell physiology. Here, we find that when applied to apical membranes of the human intestinal cell line T84, cryptdin 3 (Cr3) induces secretion of the proinflammatory cytokine interleukin 8 (IL-8) in a dose-dependent manner. The induction of IL-8 secretion is specific to the cryptdins that form channels in mammalian cell membranes because cryptdin 4, which does not form pores in T84 cells, does not induce IL-8 secretion. Cr3 induces inflammatory cytokine secretion by activating NF-kappaB and p38 mitogen-activated protein kinase in a Ca2+-dependent manner, but influx by extra-cellular Ca2+ is not involved. Unlike other known inflammatory agonists, signal transduction by Cr3 occurs slowly, suggesting a novel mechanism of action. These results show that selective cryptdins may amplify their roles in innate immunity by acting as novel paracrine agonists to coordinate an inflammatory response with the antimicrobial secretions of Paneth cells.

Blotting, Western↗

PubMed2003

Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling.

Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl(-) secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca(2+)-dependent Cl(-) conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca(2+) transients via activation of a long-lived, store-operated Ca(2+) entry pathway. The enhanced intracellular Ca(2+) signal is associated with uncoupling of the Cl(-) conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca(2+) signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.

Adult↗