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Enhanced airway smooth muscle (ASM) contractility contributes to increased resistance to airflow in diseases such as bronchitis and asthma that occur in passive smokers exposed to secondhand smoke. Little information exists on the cellular mechanisms underlying such airway hyperreactivity. Sputum samples of patients with chronic sinusitis, bronchitis, and asthma show increased concentrations of growth factors called neurotrophins, including brain-derived growth factor (BDNF), but their physiological significance remains unknown. In human ASM, we tested the hypothesis that BDNF contributes to increased contractility with cigarette smoke exposure. The exposure of ASM to 1% or 2% cigarette smoke extract (CSE) for 24 hours increased intracellular calcium ([Ca 21 ] i ) responses to histamine, and further potentiated the enhancing effects of a range of BDNF concentrations on such histamine responses. CSE exposure increased the expression of the both high-affinity and lowaffinity neurotrophin receptors tropomyosin-related kinase (Trk)-B and p75 pan-neurotrophin receptor, respectively. Quantitative ELISA showed that CSE increased BDNF secretion by human ASM cells. BDNF small interfering (si)RNA and/or the chelation of extracellular BDNF, using TrkB-fragment crystallizable, blunted the effects of CSE on [Ca 21 ] i responses as well as the CSE enhancement of cell proliferation, whereas TrkB siRNA blunted the effects of CSE on ASM contractility. These data suggest that cigarette smoke is a potent inducer of BDNF and TrkB expression and signaling in ASM, which then contribute to cigarette smoke-induced airway hyperresponsiveness.Keywords: neurotrophin; asthma; TrkB; environmental tobacco exposure; secondhand smoke Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) can be triggered or exacerbated by cigarette smoke and secondhand smoke exposure (1-4). Furthermore, in people with preexisting airway diseases such as asthma, acute exposure to cigarette smoke can produce a bronchospastic response. Considerable evidence already exists that airway inflammation occurs with cigarette smoke exposure, and contributes to airway disease even in passive smokers. Regardless of the underlying causes for airway inflammation (of which there are many), increased airway smooth muscle (ASM) contractility is certainly a key factor contributing to the pathological airway narrowing and increased airflow resistance observed in asthma and bronchitis. Although smoke exposure is recognized to increase airway contractility, the mechanisms by which cigarette smoke enhances ASM contractility remain under investigation.In the nervous system, growth factors called neurotrophins (NTs) are well recognized for their role in the generation, growth, and maintenance of different neuronal populations (5-9). Both short-term (seconds or minutes) and long-term (hours or days) effects of NTs on nuclear and cytosolic signals have been recognized as favoring increased synaptic transmission and plasticity, cell proliferation, and surviva...

Objective Polycystic kidney disease (PKD) is a common cause of end stage renal failure and many of these patients suffer vascular dysfunction and hypertension. It remains unclear whether PKD is associated with abnormal microvascular structure. Thus, this study examined the renovascular structure in PKD. Methods PKD rats (PCK model) and controls were studied at 10 weeks of age, and mean arterial pressure (MAP), renal blood flow and creatinine clearance were measured. Microvascular architecture and cyst number and volume were assessed using micro-computed tomography, and angiogenic pathways evaluated. Results Compared to controls, PKD animals had an increase in MAP (126.4±4.0 vs. 126.2±2.7mmHg) and decreased clearance of creatinine (0.39±0.09 vs. 0.30±0.05ml/min), associated with a decrease in microvascular density, both in the cortex (256±22 vs. 136±20 vessels per cm2) and medullar (114±14 vs. 50±9 vessels/cm2) and an increase in the average diameter of glomeruli (104.14±2.94 vs. 125.76±9.06 mm). PKD animals had increased fibrosis (2.2±0.2 fold vs. control) and a decrease in the cortical expression in hypoxia inducible factor 1-α and vascular endothelial growth factor. Conclusion PKD animals have impaired renal vascular architecture, which can have significant functional consequences. The PKD microvasculature could represent a therapeutic target to decrease the impact of this disease.

Polycystic kidney disease (PKD) is a common cause of end stage renal failure, for which there is no accepted treatment. Progenitor and stem cells have been shown to restore renal function in a model of renovascular disease, a disease that shares many features with PKD. The objective of this study was to examine the potential of adult stem cells to restore renal structure and function in PKD. Bone marrow-derived mesenchymal stromal cells (MSCs, 2.5×105) were intrarenally infused in 6 week-old PCK rats. At 10 weeks of age, PCK rats had an increase in systolic blood pressure (SBP) vs. controls (126.22±2.74 vs. 116.45±3.53mmHg, p<0.05) and decreased creatinine clearance (3.76±0.31 vs. 6.10±0.48µl/min/g, p<0.01), which were improved in animals that received MSCs (SBP: 114.67±1.34mmHg, and creatinine clearance: 4.82±0.24µl/min/g, p=0.001 and p=0.003 vs. PKD, respectively). MSCs preserved vascular density and glomeruli diameter, measured using micro-computed tomography. PCK animals had increased urine osmolality (843.9±54.95 vs. 605.6±45.34mOsm, p<0.01 vs. control), which was improved after MSC infusion and not different from control (723.75±56.6mOsm, p=0.13 vs. control). Furthermore, MSCs reduced fibrosis and preserved the expression of the pro-angiogenic molecules, while cyst size and number were unaltered by MSCs. Delivery of exogenous MSCs improved vascular density and renal function in PCK animals, and the benefit was observed up to four weeks after a single infusion. Cell-based therapy constitutes a novel approach in PKD.

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