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A (chronic) Very Low Dose Endotoxin Exposure Might Be As Dangerous As An Acute One

Discussion in 'Scientific Studies' started by Amazoniac, Jul 4, 2016.

  1. Amazoniac

    Amazoniac Member

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    Treehuggers,

    @haidut forced me to post this study with the following comments:

    This, unlike the majority of studies on the effects of LPS, was done using a very low dose of endotoxin; according to them, something that is compatible with the circulating levels seen in chronic metabolic diseases in humans.

    http://www.jbc.org/content/289/23/16262.full.pdf

    "Mechanistically, a super-low dose of endotoxin results in a mildly sustained activation of pro-inflammatory mediators without the activation of anti-inflammatory mediators, allowing low-grade, non-resolving inflammation to persist (7). In contrast, medium to higher dosages of LPS induce a robust yet transient immune response where both pro- and anti-inflammatory mediators are activated, providing the host with a compensatory mechanism to resolve inflammation and maintain homeostasis (8)."

    According to them, in acute inflammation, cell-death occurs in a more ordered way; whereas in chronic low-grade inflammation, an alternative pathway of cell death is predominant, that involves mitochondrial fission, oxidative stress and a vicious inflammatory cycle.

    “Higher dosages of LPS are known to trigger compensatory tolerance in innate immune cells, as reflected in the reduced expression of pro-inflammatory cytokines as well as increased mitochondrial bioenergetics and function (8). However, the mechanisms responsible for the non-resolving, low-grade inflammation initiated by a super-low dose of LPS are not well understood. To address this critical question, we examined the effects of a super-low dose of LPS on cellular necroptosis as well as key upstream signaling pathways. We demonstrate that a super-low dose of LPS potently induces necroptosis through an interleukin 1 receptor-associated kinase 1 (IRAK-1)-dependent pathway that leads to selective activation of Drp1 and degradation of Mfn1 [protein involved in stabilization of mitochondrial fission].”

    They first tested how proteins related to inflammation are affected by a very low dose and a regular dose. The activation of those proteins was sustained for longer on the former, but resolved much earlier on the latter.

    “Low-grade inflammation induces cellular stress and death, which, in turn, may sustain non-resolving inflammation (26).”

    They then tested and found that a very-low dose of LPS doesn’t induce the triggering step in the cascade of controlled cell death. They also observed that when they purposely inhibit that step, it amplifies the damage caused by a very low dose of LPS. Which suggests that when necroptosis happens in animals, the damage is worse.

    With the very low dose, the mitochondria also changed its shape: “a super-low dose of LPS induced the conversion of an elongated mitochondrial morphology to a fragmented one”, “WT BMDMs [mice blood cells derived from bone marrow] treated with a super-low dose of LPS exhibited fractionated mitochondria, potentially because of increased fission, compared with the untreated cells.”

    Later, the researchers, knowing that a specific enzyme (associated with inflammatory cytokines) can alter the cascade of events that leads to one of the two aforementioned pathways, tested how the response was in normal and knockout (for that enzyme) mice blood cells behaved in response to the very low dose of LPS, because it's apparently the exact enzyme involved in chronic low-grade inflammation. The result was as expected, when the enzyme is not present, they couldn’t induce necroptosis because it depends on it. The reason they investigated the involvement of the enzyme is due to the fact that low-grade inflammation elicits a different type of response, again, one of the steps requires that enzyme. Also in chronic low-grade inflammation, as induced by small doses of endotoxin, disordered destruction and lacking enough counter-regulatory protection are common.

    “Our findings indicate that a super-low dose of LPS selectively induces cell stress and necroptosis. This effect may be facilitated by enhanced mitochondrial fission, reduced fusion mediated by reduced Drp1 phosphorylation, and Mfn1 degradation. All of these processes are IRAK-1-dependent. This conclusion is corroborated by various molecular and cellular lines of evidence. First, a super-low dose of LPS triggers low-grade cellular stress and necroptosis in wild-type but not in IRAK-1-deficient macrophages. Second, a super-low dose of LPS leads to mitochondrial fission, the dephosphorylation and activation of Drp1 in macrophages dependent upon IRAK-1. Third, a super-low dose of LPS degrades Mfn1, a protein involved in maintaining proper mitochondrial fusion and antagonizing the function of Drp1, in an IRAK-1-dependent manner.”

    “Our data indicate that a super-low dose of endotoxin is highly potent in inducing macrophage necroptosis instead of apoptosis. Unlike programmed apoptotic cell death, which resolves inflammation, necroptosis is associated with non-resolving inflammation and persistent activation of stress kinases such as JNK (41, 42). As a consequence, cell necroptosis is associated with a multitude of inflammatory complications such as atherosclerosis, reduced wound repair, inflammatory bowel diseases, and ischemic injury (13, 42–46).”

    “Our data indicate that a super-low dose of LPS not only activates Drp1 [mitochondrial disturbance] but also reduces the protein levels of Mfn1 [stabilization, protective, counter-regulatory] through an IRAK-1[enzyme]-dependent pathway.”


    --
    “When a cell is stimulated, it responds, and the response requires energy. The stronger and more continuous the stimulus, the more energy the cell needs to continue responding. In some conditions, cells can desensitize themselves, to survive in the presence of continuous stimulation or irritation, but otherwise they are killed when they don't have enough energy to keep responding.” From Cancer: disorder and energy


    There's nothing cute about chronic low-grade inflammation, seducers. When immunity is chronically and excessively activated, it diverts resources, creates damage and wreaks havoc over time.

    A critical review of human endotoxin administration as an experimental paradigm of depression
    From inflammation to sickness and depression: when the immune system subjugates the brain
     
  2. misery guts

    misery guts Member

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    Thanks for that. Does it appear as though the body is doing something disadvantageous here, or is the lack of resolution in the inflammatory response perhaps just reflective of the body recognising that a constant low level insult is going to require a constant response?

    "something that is compatible with the circulating levels seen in chronic metabolic diseases in humans."

    I don't want to sound pedantic but I've seen quite a large number of diseases on here associated with endotoxin so just out of curiosity, are you saying ALL chronic metabolic diseases?
     
  3. Hugh Johnson

    Hugh Johnson Member

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    That's very interesting. Especially considering how most of us do a lot of anti-inflammatory things. I'm thinking exercise could be a safe way to induce temporary inflammation and end the chronic response.
     
  4. misery guts

    misery guts Member

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    this was my initial thought too, but are you not just preventing your body from neutralizing the endotoxin, leaving it to do whatever it is when left unchecked (I don't know but presumably something terrible :/ )
     
  5. Hugh Johnson

    Hugh Johnson Member

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    I'm not following.
     
  6. OP
    Amazoniac

    Amazoniac Member

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    Lord, I'm merely sharing so that other people more knowledgeable can give their opinion.
    However, it seems that a very-low dose of endotoxin doesn't seem to trigger an anti-inflammatory response because it should not pose as a systemic threat. The problem is when you're exposed to them chronically.
    Regarding endotoxin and metabolic diseases, I also don't know, but what I can comment is that it's not clear if the endotoxin is a cause or a consequence of poor metabolism. Like most things, one feeds the other; which is probably why it's difficult to stop that cycle by taking average measures and not resorting to therapeutic things.
    An occasional exposure to anti-inflammatory substances like aspirin probably will give you the therapeutic kick, however if you're exposed to it chronically, it seems more risky.
     
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