The inflammation found in Crohn’s is considered to be caused by some form of hyper immune/inflammatory response. However, this is a very broad definition and does not really explain what’s seen in the guts of Crohn’s suffers. For example, the whole gut is not inflamed and the inflammation is not uniformly (evenly) spread out. In fact, if you look carefully at early and late stage Crohn’s, you’ll see a number of small areas of trauma. It’s better to refer to the areas of trauma as wound sites. Here’s the definition of a wound: an injury, especially one in which the skin or another surface is torn, pierced, cut, burned, or otherwise broken.

Have a look at the image below.

As you can see in the late-stage Crohn’s image, the entire gut is NOT inflammed but there are many wound sites.

The most important hormone (compound) inherently connected to Crohn’s is Tumor Necrosis Factor (TNF) because TNF blockers have found to induce remission or reduce disease activity.

Here’s wiki’s definition of TNF: “Tumor necrosis factor (TNF, cachexin or cachectin formerly known as tumor necrosis factor-alpha or TNF-α) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by other cell types as well. The primary role of TNF is in the regulation of immune cells. “

Elevated or excessive amounts of TNF are found in Crohn’s sufferers’ guts (in fact, it’s found in inflamed and non-inflamed areas).

“RESULTS: Elevated TNF-alpha, IL-1beta, IL-6, and acute phase proteins were observed in patients with Crohn’s disease.”: http://www.ncbi.nlm.nih.gov/pubmed/12358255

“The serum of Crohn’s patients contained elevated levels of TNF-alpha (34±1.80 pg/mL)”: http://www.ncbi.nlm.nih.gov/pubmed/21658307

“cultures of intestinal biopsy specimens taken from areas of affected mucosa from patients with Crohn’s disease spontaneously produced increased amounts of TNF-alpha, IL-1 beta, and IL-6 compared with controls”: http://gut.bmj.com/content/39/5/684

The most effective drug to-date for inducing Crohn’s remission is Humira (adalimumab). Interestingly, Humira is a TNF blocker. Other TNF blockers that have demonstrated potential for treating Crohn’s include Etanercept and Remicade (infliximab).

“Etanercept may be effective in Crohn’s disease refractory to standard therapy.”: http://www.ncbi.nlm.nih.gov/pubmed/11569676?dopt=Abstract

“The present experience with infliximab in clinical practice confirms its efficacy, in particular in inflammatory/refractory Crohn’s disease and its safety, at least, in short-term follow-up.”: http://www.ncbi.nlm.nih.gov/pubmed/12132788

Simply put, TNF blockers work by inhibiting Tumor Necrosis Factor. But what’s really interesting about TNF blockers (inhibitors) is there potential to “remarkably” accelerate wound healing. Consider the two studies below using Etanercept and Remicade.

In rats treated with a selective TNF-inhibitor it was accidentally found that wound healing was improved and scar/adhesion formation was reduced… Three pigs were treated with infliximab (a selective TNF inhibitor) and three pigs received saline and served as control. After 7 days the laminectomy site was evaluated by a macroscopical analysis and specimens of skin and muscle tissue over the laminectomy were processed for histology. Skin, fascia, muscle and bone healing was remarkably better in the pigs treated with infliximab… The present pilot investigation may thus indicate that an inhibition of pro-inflammatory cytokines may increase wound-healing rate and reduce scar formation/adhesion. http://www.ispub.com/journal/the-internet-journal-of-spine-surgery/volume-5-number-2/inhibition-of-tumor-necrosis-factor-may-improve-wound-healing-and-reduce-scar-formation-following-laminectomy-a-pilot-study-in-pigs.html

Thermal injury may lead to systemic inflammatory response, and multiple organ failure. This study was designed to determine the possible protective effect of etanercept treatment against oxidative damage in the lung tissue induced by burn injury… Similarly, serum TNF-α, IL-1β and LDH were elevated in the burn group as compared to control group. On the other hand, etanercept treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by thermal trauma. Findings of the present study suggest that etanercept possesses an anti-inflammatory effect on burn-induced pulmonary damage and may be beneficial in thermal trauma. http://www.marmarapharmaceuticaljournal.com/text.php3?id=276

Considering Crohn’s have increased levels of TNF, and anti-TNF agents are effective against Crohn’s (in one form or another) and potentially promote rapid healing, is Crohn’s really about non-healing wounds? Is the excess TNF preventing the wounds from healing? The paper below suggests “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”.

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.
Source: http://www.mendeley.com/research/refractory-ulcers-the-role-of-tumor-necrosis-factoralpha/#page-1

As mentioned above, the entire Crohn’s gut is not inflamed but comprises a number of wound areas (often blisters). The wound areas don’t seem to heal in most sufferers but they can certainly vary in size.

If Crohn’s is really about non-healing wounds, two questions arise:

1. What causes the wounds in Crohn’s guts; and
2. What causes the elevated/excess amount of Tumor Necrosis Factors (TNF) in Crohn’s?

I’ll answer both of these questions very soon and show how they are inextricably linked to MAP!