Wrt is driven by inflammation

 

Med Hypotheses. 2016 Aug;93:1-4. doi: 10.1016/j.mehy.2016.05.004. Epub 2016 May 7.

Is osseointegration inflammation-triggered?

Abstract

Bioinert endosteal implants cause a foreign body reaction, whereas bioactive ones cause osseointegration. However, the mechanisms responsible for the two modi of host response remain unclear. COX-2(-/-) animal models showed the dependence of osseointegration on prostaglandins. PGE2, a product of COX-2, augments Wnt signalling, a pathway that promotes the regeneration in many types of tissues. Recently, we demonstrated the ability of bioactive implants to recruit neutrophils and to trigger neutrophil extracellular traps (NETs), which are a potent source of PGE2. In bioinert implants no PGE2 release has been ascertained. Collectively, these findings suggest that osseointegration might be the host response to bioactive implants, novel and quite different to the so-called foreign body reaction.

AND…

Br J Pharmacol. 2016 Jan;173(2):319-31. doi: 10.1111/bph.13373. Epub 2015 Dec 16.
Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP.
Abstract
BACKGROUND AND PURPOSE:

Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE2 , a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear.

EXPERIMENTAL APPROACH:

The effects of PGE2 , agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model.

KEY RESULTS:

PGE2 inhibited PMA-induced NET formation in vitro through EP2 and EP4 Gαs-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP2 receptor agonist.

CONCLUSIONS AND IMPLICATIONS:

PGE2 inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis-related diseases.

AND…

Nat Med. 2015 Jul;21(7):815-9. doi: 10.1038/nm.3887. Epub 2015 Jun 15.
Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.

Abstract

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

Post Comment