title: The Opposite Expected Effect of p38 Inhibitors on Fat Graft Survival.
abstract: BACKGROUND
  Fat grafting is an increasingly popular method of augmentation/reconstruction of soft tissue defects. However, the clinical unpredictability and high resorption rates of the grafts remain problematic. Cellular stress from the harvest and the ensuing ischemic episode may be the cause of this. Cellular stress activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In response to cellular stress, the p38 pathway can lead to apoptosis and can negatively regulate cell proliferation. Inhibition of p38 in ex vivo experiments has been shown to promote the expansion of human cord blood hematopoietic stem cell and improve the adipogenesis process through its upstream regulator, Shp2. Because of its wide-ranging cell regulation and antiinflammatory properties, large-scale clinical trials using p38 inhibitors are also currently being performed, especially for therapeutic effect in chronic obstructive pulmonary disease and asthma. The rationale for our study was that the treatment of fat grafts with p38 inhibitor would (a) prevent apoptosis of adipose-derived stem cells in the fat grafts, (b) increase adipose-derived stem cells proliferation, and (c) stimulate the release of several angiogenic factors and promote revascularization.
  
  
  METHODS
  Clinical and histological testing was performed on 5 fat-transplanted (1 mL) CD-1 nude mice compared with the test group of 5 mice, which were injected with a p38 MAPK inhibitor at 1, 3, 6, and 9 days after the fat transplantation.
  
  
  RESULTS
  The weights and volumes of the control group grafts were significantly higher than those of the p38 MAPK inhibitor-treated grafts. Average volume resorption was 36% in the control group and 92% in the test group. Histological evaluation of the grafts revealed significantly improved integration, with a significant reduction of fibrosis and inflammation in the control group versus the treated group.
  
  
  CONCLUSIONS
  This preliminary study suggests that as opposed to our hypothesis, inhibition of p38 significantly increases fat graft resorption. The dramatic effects observed in our study may suggest that p38 may act differently on the numerous cell types that constitute the fat graft, and further investigation is necessary.
authors.affiliation: Department of Plastic Surgery, Rambam Health Care Centre, Haifa, Israel.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Filson
authors.affiliation: Department of Plastic Surgery, Rambam Health Care Centre, Haifa, Israel.
authors.forename: Aviad
authors.initials: A
authors.lastname: Keren
authors.affiliation: Department of Plastic Surgery, Rambam Health Care Centre, Haifa, Israel.
authors.forename: Nyra
authors.initials: N
authors.lastname: Goldstein
authors.affiliation: Department of Plastic Surgery, Rambam Health Care Centre, Haifa, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Ullmann