A brief review of molecules associated with one or more stages of DR.
A better understanding of the molecular mechanisms of onset and the temporal sequence of the different pathogenic components of diabetic retinopathy (DR) and diabetic macular oedema (EMD), is one of the challenges currently facing researchers and specialists in this field. Indeed, framing the state of progression in which the patient with DR or EMD finds himself is fundamental to an timely diagnosis and to tailor the choice of therapeutic treatment to the patient's needs.
In this regard, it is important to remember that the pathogenesis of DR, and consequently EMD, is multifactorial and may depend on:
- oxidative stress phenomena;
- angiogenetic processes;
- inflammatory processes.
The role of the inflammatory process in the onset of DR is now well established, as this disease can be considered one of the manifestations of a systemic inflammatory state that occurs in individuals with diabetes mellitus (DM). However, there is still an open debate about the exact time sequence and contribution of these processes to the establishment of EMD. In particular, it remains to be clarified whether angiogenesis mechanisms, characterised by an over-expression of the vascular endothelial growth factor (VEGF-vascular endothelial growth factor), are a cause or a consequence of inflammation.
How is the inflammatory process triggered?
It has not yet been clarified which trigger signal is capable of triggering the inflammatory response and whether this is unique or depends on various factors. However, it has recently been proposed that it is precisely activation of the retina's immune system, and in particular microglia, to initiate the inflammatory process.
Have molecules associated with a specific stage of DR been identified?
A crucial role in the RD associated with serous retinal detachment appears to be carried out by the protein p38 mitogenic kinase (MAPK)itself involved in theover-regulation of interleukin-6. In fact, it has been hypothesised that the increase ininterleukin-6 can provoke an inflammatory reaction in the outer portion of the retina, resulting in the destruction of the outer membranes.
Another study, however, found an association between proliferative DR and a molecule called 'soluble factor sCD14'. In particular, the soluble factor sCD14, in addition to inflammatory molecules commonly associated with the onset of microvascular complications such as the interleukine (IL-1b, IL-6, IL-8), the vascular adhesion molecule-1, integrin b-2 (CD-18) and the monocyte chemoattractant molecule 1 (MCP-1), was recently related to the inflammatory process underlying the proliferative phase since it has been identified at high concentrations in EMD patients, leading to the hypothesis that it may be involved in the over-expression of interleukin IL-8 and the MCP-1 molecule, which, as we have already mentioned, are two of the main factors involved in the inflammatory process.
Have new 'inflammatory molecules' been identified?
To date, several mediators of inflammation involved in the RD and EMD development process. Nitric oxide, cyclooxygenase-2 and a cascade of cytokines are the pro-inflammatory molecules that can be hyper-produced by Muller cells, the main glial cells of the retina, as a result of the common hyperglycaemic conditions that occur in DM patients.
Furthermore, some authors have identified the inflammatory intercellular adhesion molecule-1 (ICAM-1-Intercellular Adhesion Molecule 1), the cause of the leucostasis condition of the retinal capillaries and the activation of factors normally involved in the onset of diabetic microangiopathic complications. It appears, in fact, that the activation of this molecule may be consequent to the marked imbalance between pro-angiogenic and anti-angiogenic factors, typical of DR and EMD, which leads to a drastic increase in vascular endothelial growth factor, which in turn leads to an increase in the expression of ICAM-1.
An analysis of the most recent literature has shown that a essential role in the process inflammatory role of DR is played by thecell apoptosis. In this context, a real molecular structure has been identified, called 'inflammasome' which would act as a catalyst for inflammation. The inflammasome, or even NLRP3It consists of a complex of proteins, including a sensor protein (NLRP3) and several caspases, molecules that mediate the process of programmed cell death.
Several studies show that following theInflammasome activation and the consequent caspase release a strong inflammatory response due to the conversion of certain interleukins, in particular pro-IL-1b and pro-IL-18, to their active form. These results were later confirmed, as the deactivation of the inflammasome, through genetic mutations, led to a decrease in pro-inflammatory moleculesand the consequent decrease in vascular permeability.
In the light of this evidence, it is therefore clear the crucial importance of inflammatory processes in the onset of DR and the oedematous state of EMD, if not properly treatedcould result in the reduction or total loss of visual capacitysubstantially reducing the patient's quality of life.
Thus, patient management through a therapeutic treatment which has as objective the reduction or elimination of the inflammatory component is necessary where this is preponderant in order to limiting the progression of DR into EMD and any reduction in visual acuity.
Bibliography
- Romero-Aroca Pedro et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. Journal of Diabetes Research. 2016, Article ID 2156273
- Sayon Roy et al. Mechanistic Insights into Pathological Changes in the Diabetic Retina Implications for Targeting Diabetic Retinopathy. The American Journal of Pathology, Vol. 187, No. 1 (2017).
- Wei Chen. Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline. Inflamm Res. 66(2):157-166 (2017)
- Umazume K et al. Effects of soluble CD14 and cytokine levels on diabetic macular oedema and visual acuity. Retina Phila Pa 33: 1020-1025 (2013)
Dr. Carmelo Chines
Direttore responsabile
English 
Italian