Mast cell chymase is a possible mediator of neurogenic bladder fibrosis

Howard, Pamela S.; Renfrow, David; Schechter, Norman M.; Kucich, Umberto

doi:10.1002/nau.20032

Cited by 19 publications

(18 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The presence of chymase, a proteolytic enzyme, and the cleavage and activation of TGF-β have been associated with the development of scleroderma or systemic sclerosis of the skin [33,35]. The presence of increased mast cell numbers has also been observed after tissue injury in patients with fibrodysplasia ossificans progressiva, a disease marked by heterotopic ossification [38].…”

Section: Discussionmentioning

confidence: 99%

Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty

Freeman

Parvızı

Valle

et al. 2010

Fibrogenesis Tissue Repair

View full text Add to dashboard Cite

BackgroundIdiopathic arthrofibrosis occurs in 3-4% of patients who undergo total knee arthroplasty (TKA). However, little is known about the cellular or molecular changes involved in the onset or progression of this condition. To classify the histomorphologic changes and evaluate potential contributing factors, periarticular tissues from the knees of patients with arthrofibrosis were analyzed for fibroblast and mast cell proliferation, heterotopic ossification, cellular apoptosis, hypoxia and oxidative stress.ResultsThe arthrofibrotic tissue was composed of dense fibroblastic regions, with limited vascularity along the outer edges. Within the fibrotic regions, elevated numbers of chymase/fibroblast growth factor (FGF)-expressing mast cells were observed. In addition, this region contained fibrocartilage and associated heterotopic ossification, which quantitatively correlated with decreased range of motion (stiffness). Fibrotic, fibrocartilage and ossified regions contained few terminal dUTP nick end labeling (TUNEL)-positive or apoptotic cells, despite positive immunostaining for lactate dehydrogenase (LDH)5, a marker of hypoxia, and nitrotyrosine, a marker for protein nitrosylation. LDH5 and nitrotyrosine were found in the same tissue areas, indicating that hypoxic areas within the tissue were associated with increased production of reactive oxygen and nitrogen species.ConclusionsTaken together, we suggest that hypoxia-associated oxidative stress initiates mast cell proliferation and FGF secretion, spurring fibroblast proliferation and tissue fibrosis. Fibroblasts within this hypoxic environment undergo metaplastic transformation to fibrocartilage, followed by heterotopic ossification, resulting in increased joint stiffness. Thus, hypoxia and associated oxidative stress are potential therapeutic targets for fibrosis and metaplastic progression of idiopathic arthrofibrosis after TKA.

show abstract

Section: Discussionmentioning

confidence: 99%

Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty

Freeman

Parvızı

Valle

et al. 2010

Fibrogenesis Tissue Repair

View full text Add to dashboard Cite

show abstract

“…13–15 Mast cells have potent mediators that can be pre-synthesized, such as granule stored molecules (eg tryptase, chymase, heparin, histamine, proteases, phospholipases, chemotactic substances and cytokines) or synthesized de novo (eg cytokines, especially interleukin-6, leukotrienes, prostaglandins, nitric oxide and tumor necrosis factor-α). 5,14 Investigators identified mast cell chymase as a possible mediator of neurogenic bladder fibrosis in patients with MM/SB 16 and others noted that LL-37 induces mast cell chemotaxis. 17 Thus, we hypothesized that LL-37 induced bladder inflammation mechanistically involves mast cells.…”

mentioning

confidence: 99%

Physiological Relevance of LL-37 Induced Bladder Inflammation and Mast Cells

et al. 2013

View full text Add to dashboard Cite

Purpose We established the physiological relevance of LL-37 induced bladder inflammation. We hypothesized that 1) human urinary LL-37 is increased in pediatric patients with spina bifida, 2) LL-37 induced inflammation occurs in our mouse model via urothelial binding and is dose dependent and 3) LL-37 induced inflammation involves mast cells. Materials and Methods To test our first hypothesis, we obtained urine samples from 56 pediatric patients with spina bifida and 22 normal patients. LL-37 was measured by enzyme-linked immunosorbent assay. Our second hypothesis was tested in C57Bl/6 mice challenged with 7 LL-37 concentrations intravesically for 1 hour. At 24 hours tissues were examined histologically and myeloperoxidase assay was done to quantitate inflammation. In separate experiments fluorescent LL-37 was instilled and tissues were obtained immediately (time = 0) and at 24 hours (time = 24). To test our final hypothesis, we performed immunohistochemistry for mast cell tryptase and evaluated 5 high power fields per bladder to determine the mean number of mast cells per mm2. Results Urinary LL-37 was 89-fold higher in patients with spina bifida. Mouse LL-37 dose escalation experiments revealed increased inflammation at higher LL-37 concentrations. Fluorescent LL-37 demonstrated global urothelial binding at time = 0 but was not visible at time = 24. Immunohistochemistry for tryptase revealed mast cell infiltration in all tissue layers. At higher concentrations the LL-37 challenge led to significantly greater mast cell infiltration. Conclusions Urinary LL-37 was significantly increased in pediatric patients with spina bifida. To our knowledge we report for the first time that LL-37 can elicit profound, dose dependent bladder inflammation involving the urothelium. Finally, inflammation propagation involves mast cells.

show abstract

“…In vitro , chymase treatment of bladder fibroblasts increases levels of types I and III collagen, and this can be prevented by denatured chymase [28] . Thus, it is possible that mast cell chymase underlies bladder fibrosis.…”

Section: Fibrosismentioning

confidence: 99%

“…Bladder fibrosis develops in patients with spina bifida, and this is associated with mast cell accumulation [28] . In vitro , chymase treatment of bladder fibroblasts increases levels of types I and III collagen, and this can be prevented by denatured chymase [28] .…”

Section: Fibrosismentioning

confidence: 99%