Increasing that MC degranulation promotes hepatic I/R injury in

Increasing
evidence suggests that MCs play a key role in IR injury (7,8, 30) In addition,
IR injury is reported to be attenuated in the genetically mast-cell deficient
rats(31,32) , although there are some  exceptions (9,10).

We
observed that rats treated with BMMSCs demonstrated a significant decrease   in flap survival compared to CEE and CEE+BMMSCs
groups. At the same time, the total number of MCs and degranulted MCs counts
were significantly increased in flaps from BMMSCSs group compared CEE -treated and
control groups. The administration of CEE after surgery can significantly
reduce the extent of flap necrosis and the  
total number of MCs and 
degranulted MCs  counts caused by
I/R . This protective effect is not seen with BMMSCs group. The protective
effect of CEE  on flap necrosis might be also
related to the decreases  in  the  
total number of MCs and 
degranulted MCs  within the flap. Our
results probably demonstrate that degranulted MCs could release some toxins that
must mediate a component of tissue injury. Consistency Yang et al evaluated the
role of MCs in hepatic I/R injury in rat. 
They showed that both the stabilization of MCs with cromolyn and
depletion of MCs with compound 48/80 facilitate protection against liver damage
after I/R. Yang et al concluded that  MC
degranulation promotes hepatic I/R injury in rats(7). Georgopoulos et
al investigated whether hydroxyzine can reduce the necrotic area in I/R injury
in epigastric rat skin flaps and to compare its role with cimetidine and
vitamin C. Georgopoulos et al suggested 
that administering hydroxyzine in rat epigastric skin flaps before
reperfusion may attenuate necrosis, neutrophils and MC counts(8). Cordeiro et al
examined  the role of MCs and their
principal product, histamine, in I/R injury in an ischemic epigastric island
skin flaps . Cromolyn
sodium, diphenhydramine, and cimetidine were administered to the flaps.  Cordeiro et al evaluated flap survival, MC
count, neutrophil count, and myeloperoxidase levels. Cordeiro et al observed
that the animals treated with diphenhydramine and cimetidine demonstrated  significant decrease in flap necrosis. Both
neutrophil and MC counts were significantly decreased in flaps from
antihistamine-treated  versus both
control and cromolyn sodium-treated groups. Cordeiro et al concluded that the
protective effect of antihistamines on flap necrosis might be related to the
decrease in neutrophils and, possibly, MCs within the flap (30). Rork et al
stated that MCs in the heart contribute to reperfusion injury following
myocardial ischemia. Since the activation of A2A adenosine receptors (A2AARs)
inhibits reperfusion injury, Rork et al hypothesized that ATL146e (a selective
A2AAR agonist) might protect hearts in part by reducing cardiac MCs
degranulation. Rork et al suggest that in ex vivo, buffer-perfused hearts, MCs
degranulation contributes to I/R injury. In addition, their  data suggest that A2AAR activation is
cardioprotective in the isolated heart, at least in part by attenuating
resident MCs degranulation(31).Andoh et al studied the role of mucosal type MCs
(MMC) in the development of intestinal I/R 
in Ws/Ws rats. Ws/Ws rats have a small deletion of the c-kit gene, and
are deficient in both mucosal and connective tissue-type MCs. Andoh et al
reported that  their results provide
direct evidence for the positive role of MCs in the pathogenesis of intestinal
ischaemia-reperfusion injury(32).
In
this regard most current knowledge about the function of MCs in I/R injury
relate to degranulation, which correlates strongly with the severity of IR
injury in many organs(30,33,34,35).
Shortly
after I/R, MCs release many chemicals which can cause injury during organ I/R
by degranulating or synthesizing new chemicals(28).

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On
the other hand some studies have shown positive effect of MCs in ischemic
models. Nishioka
et al  evaluated  the effect of LLLT and LED on the viability
of RSFs(10?×?4 cm)  in rats. They
observed  percentage of necrosis was
significantly lower in the LED, and LLLT 
groups compared to control  group.
Concerning blood vessels and MCs numbers, only the animals in the LED  group 
showed significant increase compared to control group  in the skin sample of the transition line (9). Coneely et al
investigated the importance of MC degranulation in anastomotic healing and to
assess whether a promoter of MC degranulation could increase anastomotic
healing in poorly perfused bowel. A colo-colonic anastomosis was formed in each
animal. Four days later, following ehthanization, the strength of the
anastomosis was assessed. They reported MC stabilisation reduced anastomotic
healing in normally perfused bowel. Hypoperfused bowel resulted in reduced
anastomotic strength however the addition of a MC degranulating agent increased
healing in hypoperfused bowel to levels comparable with control. Coneely et al
concluded that MC degranulation is essential for early anastomotic healing. Healing
is reduced in hypoperfused bowel but the administration of a MC degranulation
agent can compensate for the adverse effects of a poor blood supply on
anastomotic healing(10).

According
to previous studies (11,12,13) positive effect of stem cell therapy on skin
flap has been reported. Consequently in the current study the effect of BMMSC
and CEE in combination or alone were studied. Interestingly the CEE  was more effective statistically compared to
the BMMSCs and CEE+BMMSCs. It is not clear why BMMSCs treatments  flaps has not significantly increased flap
survival compared to CEE treatment. Moreover it was not clear how BMMSCs significantly
induced MC degranulation.

Base
on a recent study, BMMSCs should prevent MC function and degranulation(36). Brown et al
stated that the MC is an important inflammatory cell. And the MCs  has resisted therapeutic attempts to alter
its role in disease(37). In addition BMMSCs 
have been reported to alter allergic inflammation in vivo. In this
context Brown et al investigated the interaction between mouse BMMSCs  and mouse bone marrow-derived MCs in culture
system and in an animal model. MC degranulation, cytokine production and
chemotaxis were evaluated. Brown et al revealed that BMMSCs will effectively
suppress specific MCs functions in vitro as well as in vivo. Further, Brown et al
found that these inhibitory effects were dependent on up-regulation of
cyclooxygenase-2 (COX2) in BMMSCs; and were facilitated through the activation
of Prostaglandin E2 receptor 4 (EP4) receptors on MCs. It seems Brown study was
performed in normal oxygenation pressure(33). However stem cell therapy in
current study was performed under ischemic condition and in an experimental
model  of I/R.

CONCLUSION

The
biostimulatory effect of BMMSCS, CEE, and CEE+BMMSCs promptly in this
scientific experiment was presented by significant increase in survival part of
flap, and blood vessel sections compared to the control group. In case of flap
survival, the CEE group was more effective statistically compared to the
BMMSCs, and BMMSCs+CEE groups. Moreover type two MCs (complete degranulation
state of  MCs) and total number of MCs in
BMMSCs group were significantly higher than CEE, CEE+BMMSCs, and control
groups. It
seems there is a relation exist between significant increased numbers of type
two MCs in BMMSCs group, and also significant decreases of flap survival in
this group. We hypothesized that there was an interaction between MCs and
BMMSCs in the ischemic tissue in BMMSCs groups, and  MCs productions induced  an inhibitory effect on survival of RSF
compared to CEE group. We concluded that MC productions induced an inhibitory effect on
survival of the RSFs.