Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction, inflammation and fibrosis of skin and internal organs. An imbalance of pro-angiogenic factors and angiogenesis inhibitors has been implicated in the progression of vascular damage and fibrosis. In SSc, scleroderma renal crisis, isolated reduced glomerular filtration rate (GFR) and abnormal renal vascular resistance indices were observed. The subclinical renal vasculopathy is most frequent and it is characterized by increased renal resistive index (RRI) and reduction of parenchymal thickness with impaired function. Inflammation may lead to glomerulosclerosis, vascular damage and fibrosis. The interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) axis plays an important role in the diabetic nephropathy. The persistence of inflammation activates the production of pro-fibrotic cytokines. Failure to resolve inflammation may be linked to a reduced production of pro-resolving mediators. Resolution of inflammatory response is now considered a biosynthetically active process governed by specialized pro-resolving mediators. These chemically distinct families include lipoxins, resolvins, protectins and maresins that are biosynthesized from essential fatty acids. In SSc, there are no data about pathogenetic mechanisms of renal damage from angiogenesis to the resolution of inflammation. Primary objective of this study is to evaluate the intrarenal arterial stiffness by renal Doppler (renal resistive index) and to correlate it with renal ultrasound parameters (parenchymal thickness). Secondary objective is to evaluate the role of angiogenesis, inflammation and resolution of inflammation on SSc nephropathy. In SSc patients, serum levels of vascular endothelial growth factor, endostatin, IL-33, sST2, lipoxin A, resolvin D1 and maresin 1 will be evaluated. The identification and actions of pro-resolving mediators, conjugates in tissue regeneration, could offer new therapeutic horizons.
In SSc patients, intrarenal stiffness is increased compared to healthy controls. Doppler indices of intrarenal stiffness negative correlate with measured and estimated GFR and increase with progression of capillaroscopic damage. In addition, they are higher in SSc patients with digital ulcers. Renal resistive index is one of the independent predictors for mortality, with 0.68 as best cut-off. Intrarenal stiffness indices are high in SSc with myocardial fibrosis or increased systolic pulmonary arterial pressure (sPAP). Doppler indices of intrarenal stiffness are a reliable marker of renal vasculopathy and vascular damage of skin and internal organs. They can also be used to evaluate the therapeutic response to vasoactive drugs. In SSc, parenchymal thickness is significantly reduced compared to healthy controls. Parenchymal thickness also inversely, and yet correlates with RRI. In SSc, early renal damage is characterized by vasculopathy with normal function. The progression of renal vasculopathy leads to parenchymal thickness reduction with worsening of renal function.
The impaired angiogenesis is responsible of maintenance and progression of renal chronic ischemic damage due to failure of vessels neoformation. Chronic renal vasculopathy also results in a loss of nephrons and a reduction in the functioning renal parenchyma. We can hypothesize that, after renal chronic ischemic damage, chronic inflammation starts with the release of proinflammatory cytokines (eg IL-33). The persistence of inflammation activates the production of pro-fibrotic cytokines with renal fibrosis. Failure to resolve inflammation may be linked to a reduced production of mediators for resolution of inflammation. A major knowledge regarding regulators of resolution of inflammation is important to evaluate the role of low-level ¿sterile¿ inflammation, characterized by macrophage infiltration and localized cytokine/chemokine production, in the progression of damage on chronic diseases such as arthritis, diabetes, atherosclerosis and SSc. Stereoselective pro-resolving bioactions of lipoxins, and more recently, resolvins, protectins and maresins could be play a key, and yet unexplored, role in the pathogenesis of SSc organ damage. While protective, the acute inflammatory response when uncontrolled can lead to further tissue damage and chronic inflammation that is now widely recognized to play important roles in many commonly occurring diseases, such as cardiovascular disease, neurodegenerative diseases, metabolic syndrome and autoimmune diseases. Since the acute inflammatory response is protective, evolved to permit repair of injured tissues and eliminate invading organisms, it is ideally self-limited and leads to complete resolution of leukocyte infiltrates and clearance of cellular debris enabling homeostasis. Although resolution of inflammation was long considered a passive process, recent evidence has demonstrated that resolution of self-limited inflammation is an active process.. Resolution of inflammatory response is currently seen as a biosynthetically active process governed by specialized pro-resolving mediators. These chemically distinct families include lipoxins, resolvins, protectins and maresins that are biosynthesized from essential fatty acids from the omega-6 and omega-3 series. The active resolution phase leads to tissue regeneration in model organisms. With strategy employing unbiased local mediathors-lipidomics, genetically engineered (e.g. exudates and human cell systems), the resolution of inflammation is actively "turned on" and not simply a passive process.
The results of this study could lead to the definition of different stages of scleroderma vasculopathy in which chronic ischemic renal vasculopathy or inflammation are more evident. The prevalence of one of the two phases could orient the therapy towards targeted vasoactive or immunosuppressive treatments. Morever, data obtained in this study could help reducing the morbidity and improve the quality of life of SSc patients through the introduction of therapeutic treatments targeted to reduce the progression of chronic ischemic scleroderma nephropathy.
The identification and actions of the three families of SPMs (maresin, protectin and resolving), conjugates in tissue regeneration, could offer new therapeutic horizons in which new and engineered therapies aim to solve inflammation. A weakness of current anti-inflammatories treatments is that they eventually become immunosuppressive.