**4. Inflammation in DR**

#### **4.1 What is inflammation?**

Inflammation is non-specific response of the the body to injury or stress which includes a variety of molecular and cellular mediators. Tissue stress may lead to de-inhibition of the transcription factor nuclear factor kappa beta (NFκB) which stimulates the production of acute phase proteins, pro-inflammatory cytokines and chemokines such as TNF-α, IL-6 and IL-1B amongst others. These pro-inflammatory mediators play a major role in the unfolding of the inflammatory processes with recruitment and activation of monocytes and leukocytes. Inflammation usually resolves spontaneously in a coordinated manner, however when this fails to happen the beneficial effect of inflammation is lost and consequences ensue.

#### **4.2 Inflammation in pathogenesis of diabetic retinopathy**

If we consider diabetic retinopathy to be a disease mediated via the inflammatory pathway then anti-inflammatory medications should provide some degree of safety. This was noted in 1964 by Powell and Field who reported that patients with rheumatoid arthritis on high dose aspirin therapy tended to have a less severe form of DR [20]. Histological features of DR were less commonly noted in dogs wherein aspirin was initiated in a dose of 20-25 mg/kg/day shortly after the diagnosis of diabetes mellitus and continued for a period of 5 years [21].

Increased concentrations of inflammatory cytokines such as IL-1, IL-6, IL-8, TNF-α and MCP-1—have been reported in ocular tissues from non-proliferative DR (NPDR) patients. The accumulation of these cytokines is believed to lead to early neuronal cell death. Cytokines such as MIP-1, IL-3 and IL-1 are believed to have a role in the angiogenesis. Thus inflammation may contribute towards and precede the development of neovascularisation [22]. Cylco-oxygenase-2 (COX-2) is expressed in the retinal astrocytes in human diabetic retinas. Prostanoids generated from COX-2 lead to an increased expression of VEGF and other pro-angiogenic factors, thereby contributing to development of proliferative diabetic retinopathy [23].

In case of diabetic macular edema (DME) levels of pro-inflammatory molecules Vascular Endothelial Growth Factor (VEGF) and IL-6 are noted to be elevated as per different studies. In particular DME associated with sub-retinal fluid on OCT shows elevated levels of these cytokines [24].

#### **4.3 Diabetes and inflammation**

The signal for the initiation of inflammation in a diabetic retina is believed to be metabolic in origin. Cell death was proposed as one of the causes, however, retinal cell death in DR is primarily via apoptosis and hence may not be associated with an inflammatory response. Certain factors that contribute directly or indirectly to increased inflammation are summarised below:
