Intrapulmonary administration of a p38 mitogen activated protein kinase inhibitor partially prevents pulmonary inflammation

Hoogendijk, Arie J.; Pinhanços, Sandra S.; Poll, Tom van der; Wieland, Catharina W.

doi:10.1016/j.imbio.2012.05.027

Cited by 1 publication

(1 citation statement)

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“…Both TGFβ receptor phosphorylated Smads and the p38 mitogen-activated protein kinase (p38 MAPK) are important mediators of TGFβ-induced apoptosis [28]. To more completely inhibit TGFβ signaling, we administered both a TGFβR1 inhibitor and a p38 inhibitor prior to castration of Pb-PRL mice, and then twice a week thereafter, at a dose previously shown to block TGF signaling in mice [29, 30]. Similarly, we administered etanercept, a TNF signaling blocker active in mice [17] prior to and following castration.…”

Section: Resultsmentioning

confidence: 99%

Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Zhang

Singh

Pan

et al. 2022

Preprint

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Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGF and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGF or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

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