Posted by Dave on Jan 10, 2013
In the guts of Crohn’s sufferers, the inflammation and ulcers (including fistulas) don’t heal or heal very slowly, why?
When you cut yourself, the healing process starts within hours, and within a few days the cut is usually fully healed, so why doesn’t this happen in Crohn’s disease? What I’m about to share with you took me nearly 10 years of dedicated research. It solves the mystery of why the inflammation/ulcers/fistulas in Crohn’s do not heal or heal very, very slowly.
The explanation gets a bit technical but I twill try to keep it as simple as possible.
In medicine there are wounds they do not heal, and they are referred to as “non-healing wounds”. Here’s some random Google images of non-healing wounds (copyright of their respective owners).
There has been a lot of research into non-healing wounds. This paper discusses ‘Factors Affecting Wound Healing”.
“Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved.”
In particular it discusses the importance of immune cells (macrophages) in wound healing.
“Macrophages play multiple roles in wound healing. In the early wound, macrophages release cytokines that promote the inflammatory response by recruiting and activating additional leukocytes. Macrophages are also responsible for inducing and clearing apoptotic cells (including neutrophils), thus paving the way for the resolution of inflammation. As macrophages clear these apoptotic cells, they undergo a phenotypic transition to a reparative state that stimulates keratinocytes, fibroblasts, and angiogenesis to promote tissue regeneration (Meszaros et al., 2000; Mosser and Edwards, 2008). In this way, macrophages promote the transition to the proliferative phase of healing.”
Another paper emphasizes the important role immune cells (macrophages) play in wound healing.
“Skin wound healing is a multi stage phenomenon that requires the activation, recruitment or activity of numerous cell types as keratinocytes, endothelial cells, fibroblast and inflammatory cells. Among the latter, macrophages appear to be central to this process. They colonize the wound at its very early stage and in addition to their protective immune role seem to organize the activity of other cell types at the following stages of the healing. Their benefit to this process is however controversial, as macrophages are described to promote the speed of healing but may also favour the fibrosis resulting from it in scars. Moreover wound healing defects are associated with abnormalities in the inflammatory phase. In this review, we summarise our knowledge on what are the Wound Associated Macrophages, and how they interact with the other cell types to control the reepithelialisation, angiogenesis and the extracellular matrix remodelling. We believe this knowledge may open new avenues for therapeutic intervention on skin wounds.”
As I’ve mentioned many times before on this blog, Crohn’s sufferers have too much of a compound called TNF (tumor necrosis factor-alpha) in their guts. Numerous studies have confirmed this, here’s one.
“Crohn’s patients contained elevated levels of TNF-alpha”: Read more: http://www.ncbi.nlm.nih.gov/pubmed/21658307
And the latest research suggests that too much TNF is LINKED to non-healing wounds – wounds that don’t heal!
“Lately, much research has focused on the pro-longed inflammatory phase in non-healing wounds, especially the potential role of the normally regulated tissue necrosis factor-alpha (TNF-a). We describe data suggesting that dysregulated TNF-a is important in the pathogenesis of chronic wounds and discuss evidence that suggests normalizing dysregulated TNF-a might be a potential therapeutic target.” Read more: http://www.mendeley.com/research/refractory-ulcers-the-role-of-tumor-necrosis-factoralpha/#page-1
Now, let’s dig into this a bit more. Why would too much TNF in the guts of Crohn’s sufferers prevent the inflammation/ulcers/fistulas from healing?
This study proved that too much TNF affects immune cells’ behavior so they don’t remove the dead cells and is probably why granulomas are formed in Crohn’s.
Overall, the data suggest that macrophages in a TNF-alpha- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response.
Remember above I mentioned the research that shows immune cells (macrophages) play a crucial role in wound healing, but what happens when the immune cells are not functioning properly? When there’s too much TNF (like in the guts of Crohn’s sufferers) the study above proved they don’t function properly. So if they are not removing the dead cells (functioning properly) they are probably not repairing the inflammation/ulcers/fistulas in the guts of Crohn’s sufferers either!
Let’s dig a little deeper. Why would too much TNF prevent immune cells from repairing the inflammation? This paper shows that TNF increases the production of a compound called Macrophage Migration Inhibitory Factor (MMIF) and excess levels of MMIF have been found in Crohn’s (read more here). And it’s proven too much MMIF is linked to non-healing wounds (here).
Now, are you ready for this? MMIF plays an absolutely essential in wound healing.
“Macrophage migration inhibitory factor (MMIF): a central regulator of wound healing”. Read more here: http://www.ncbi.nlm.nih.gov/pubmed/16314470
“We have demonstrated previously that the proinflammatory cytokine macrophage migration inhibitory factor (MMIF) acts as a global regulator of wound healing”. Read more here: http://endo.endojournals.org/content/150/6/2749.long
Let me do a quick summary as my explanation got a little complex. There’s too much TNF in the guts of Crohn’s sufferers. Too much TNF increases high levels of MMIF. Too much MMIF is PROVEN to prevent wounds from healing. In Crohn’s sufferers, we have both too much TNF and too much MMIF so it’s not surprising the inflammation/ulcers/fistulas don’t heal. Reducing TNF should start the natural healing process so the inflammation heals.
In one way or another, all effective Crohn’s drugs reduce TNF levels in the gut. For example:
- Corticosteroids can improve Crohn’s and corticosteroids inhibit TNF (study).
- Naltrexone can improve Crohn’s and Naltrexone inhibits TNF (study).
- Mesalamine can improve Crohn’s and Mesalamine inhibits TNF (study).
- Enbrel, Remicade and Humira can all improve Crohn’s and all are anti-TNF drugs.
There you have it, you now know why inflammation/ulcers/fistulas don’t heal in the guts of Crohn’s sufferers!