37. 0 5 1 0 1 5
0
2 0
4 0
6 0
8 0
1 0 0
S h a m /sa lin e
S h a m /Y V A D
B u rn /s a lin e
B u rn /Y V A D
*
Osuka, A et al. A protective role for inflammasome activation following injury.
Shock. 2012. Jan;37(1):47-55.
非熱傷/生食
非熱傷/阻害薬
熱傷/生食
熱傷/阻害薬
生存率(%)
受傷後日数
インフラマソームの活性化は
生体防御に必要である
46. Ni Choilean, N. 2006. Enhanced Regulatory T Cell Activity is an Element of the Host Response to Injury. J.
Immunol. 176: 225–236.
3日目.
.
Treg細胞
7日目1日目
T細胞の分裂抑制効果を評価
普通のT細胞
56. I: immediately <1 hr
II: early <24 hrs
I II
%Total deaths%Total deaths
Time since injury
I: immediately <1 hr
II: early <24 hrs
III: late phase >7days
I II III
Classically defined, there are three phase of death after sever Injury. This was described in 1983.
First one is immediate death, including heart rupture, cervical cord disruption, and so on.
Second phase is early death, it usually due to severe blood loss from the head, respiratory system, and abdominal organs.
Third phase is delayed deaths, it often occur days or weeks after the initial injury and are the result of infection, multi organ failure or other late complications of trauma.
The tri-modal distribution of trauma deaths was first described in 1983.1,2 As a function of elapsed time after injury, deaths from traumatic injury were classified as generally falling into one of three categories
1. occur immediately or occur quickly as a result of overwhelming injury;
2. occur during the intermediate or subacute phase.These deaths occur
within several hours of the event and are frequently the result of treatable
conditions;
3. are delayed. Deaths during this phase often occur days or weeks after the
initial injury and are the result of infection, multisystem failure or other late
complications of trauma.
immediate, early, and late. Immediate deaths were those that occurred 1h after injury, making up 50% of the total; early deaths occurred within the first few hours after injury and accounted for 30%; and late deaths occurred days to weeks after injury and were 20% of all trauma deaths. Immediate deaths were largely due to neurologic injury (brain, brain stem, spinal cord) or laceration of the heart or major vessels and classified as not preventable. Early deaths were largely due to severe blood loss from the head, respiratory system, and abdominal organs. These deaths were largely treatable and therefore possibly preventable. Finally, most late deaths were due to infection and multiorgan failure. Reducing the number of injury-related deaths during each period largely relies upon expedient and optimal medical care, though less so for some periods than others. For example, injury prevention efforts are likely to be important for reducing immediate deaths whereas trauma systems should have the greatest impact for early and late deaths.
Clinical Question
なぜ外傷後に感染すると死亡率が上がるのだろう?
Research Question
外傷後に起こる免疫応答の変化とは?
ここに示すのは異なる細胞内におけるカスパーゼの定量値です。
X軸は時間、y軸はMFIを示しています。
リンパ節内のマクロファージでは、分離型カスパーゼ1p10は受傷後1時間より上昇をはじめますが、一時的なもので、4時間後をピークに減少しました。
脾臓から採取したマクロファージ及び樹状細胞内においてはリンパ節内のカスパーゼ1の上昇に引き続いてカスパーゼ1の上昇が見られました。受傷2時間後より上昇し始め、1日後をピークに正常レベルまで戻っています。P20では受傷後3日目まで高値が続きました。
These are the quantitative data in different subsets.
X axis shows time points, and Y axis shows MFI.
In Macs derived from the LNs, the expression of cleaved caspase-1 p10 increases as early as 1 hr after injury. This effect seems to be temporary, as the curve goes down after peeking at about 4 hours following injury.
Interestingly, Macs and DCs derived from the spleens show an increased expression of cleaved caspase-1 p10 following LNs caspase-1 cleavage. After 2 hr it starts increasing and the peak is 1 day, then it return to normal level, and p20 keep high level through 3 days.
それでは、熱傷後のインフラマソームの活性化は生体にとって有用なものなのでしょうか、有害なものなのでしょうか?
細胞膜透過性を有し、活性型カスパーゼ1を特異的かつ不可逆的に阻害するYVADを用いてサバイバルスタディーを行いました。
受傷2時間前にYVADを投与しその後の生存率を記録しました。
Experiment 3
Survival study following burn injury with caspase-1 inhibitor YVAD.
We wished to know, whether injury-induced inflammasome activation is good or bad.
YVAD is an cell permiable and irreversible inhibitor binds activate caspse-1 specifically.
Mice were given saline or YVAD at 2 hours before burn injury, after burn injury we observed their survival proportions.
YVADの用量を決定した後、熱傷マウスにおいてインフラマソームの活性を抑制しサバイバルスタディーを行いました。
YVAD投与群において著明な死亡率の増加を認めました。
この結果より熱傷後のインフラマソームの活性化は生体にとって有益であると考えられました。
After determining an effective does for YVAD, we tested the impact of blocking inflammasome activation on the burn injury response in mice.
We found that YVAD treatment caused significantly higher mortality in burn injured mice.
Taken together these results support the conclusion that injury-nduced inflammasome activation is protective.
Classically defined, there are three phase of death after sever Injury. This was described in 1983.
First one is immediate death, including heart rupture, cervical cord disruption, and so on.
Second phase is early death, it usually due to severe blood loss from the head, respiratory system, and abdominal organs.
Third phase is delayed deaths, it often occur days or weeks after the initial injury and are the result of infection, multi organ failure or other late complications of trauma.
The tri-modal distribution of trauma deaths was first described in 1983.1,2 As a function of elapsed time after injury, deaths from traumatic injury were classified as generally falling into one of three categories
1. occur immediately or occur quickly as a result of overwhelming injury;
2. occur during the intermediate or subacute phase.These deaths occur
within several hours of the event and are frequently the result of treatable
conditions;
3. are delayed. Deaths during this phase often occur days or weeks after the
initial injury and are the result of infection, multisystem failure or other late
complications of trauma.
immediate, early, and late. Immediate deaths were those that occurred 1h after injury, making up 50% of the total; early deaths occurred within the first few hours after injury and accounted for 30%; and late deaths occurred days to weeks after injury and were 20% of all trauma deaths. Immediate deaths were largely due to neurologic injury (brain, brain stem, spinal cord) or laceration of the heart or major vessels and classified as not preventable. Early deaths were largely due to severe blood loss from the head, respiratory system, and abdominal organs. These deaths were largely treatable and therefore possibly preventable. Finally, most late deaths were due to infection and multiorgan failure. Reducing the number of injury-related deaths during each period largely relies upon expedient and optimal medical care, though less so for some periods than others. For example, injury prevention efforts are likely to be important for reducing immediate deaths whereas trauma systems should have the greatest impact for early and late deaths.