Fibrotic diseases cause annually more than 800,000 deaths worldwide, whereof the majority accounts for lung and cardiac fibrosis. A pathological remodeling of the extracellular matrix either due to ageing or as a result of an injury or disease leads to fibrotic scars.
In the heart, these scars cause several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance, or they can even lead to death. There are several different types of cardiac scars depending on the underlying cause of fibrosis.
Cardiac fibrosis may results from acute myocardial infarction and is seen in the progression to heart failure. Improvements in the treatment of myocardial infarction have led to declining rates in mortality and morbidity in recovering post-MI patients. However, concomitant with improved patient outcome, greater numbers of patients survive the acute phases of myocardial infarction and undergo the processes associated with myocardial tissue healing. This results in abnormal expansion of myocardial extracellular matrix interstitium with many ultimately succumbing to ventricular dysfunction and, depending on the size of the initial infarct, development of congestive heart failure.
Hepatic fibrosis, NASH
Wound healing and repair of injured tissues is an essential biological process which allows directed replacement of dead or damaged cells with connective tissue after injury. The repaired area is addressed as a scar. Hence, scarring represents a survival mechanism that is conserved throughout evolution and appears to be most pronounced in humans.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed countries. The disease extends to nonalcoholic steatohepatitis (NASH), that can further progress to fibrosis and cirrhosis and is associated with an increased risk of cardiovascular mortality and type 2 diabetes mellitus. Cirrhosis due to NASH increases the risk of hepatocellular carcinoma and NASH contributes substantially to the population burden of hepatocellular cancer. The risk factors and comorbidities for NAFLD and NASH appear to be similar and include obesity, type 2 diabetes, and dyslipidemia. Further, increased age is associated with a worsened disease progression, prognosis and mortality. There is evidence suggesting male sex as a significant risk factor.
NASH generally presents as a silent disease with only minor or no symptoms. In the fatty liver, deposits of fat cause liver enlargement and inflammation. In early stages, patients feel well, but may discover upon routine serological testing that liver enzymes are elevated, thus prompting further examination. However, some patients may experience fatigue, weight loss, and weakness. These symptoms are more common in those who have advanced NASH and liver fibrosis. A patient with cirrhosis will likely experience fluid retention, muscle wasting, bleeding from the intestines, and liver failure.
The first therapeutic approach in NASH and liver fibrosis is to eradicate the underlying causes of the chronic inflammation, as far as possible. Obese patients should normalize their excessive food intake, and HBV and HCV infected patients should be treated with antivirals. Although partial reversal of liver fibrosis is observed in some cases, complete remodeling to cirrhosis can hardly be prevented. There are currently no approved therapies for NASH and liver fibrosis. The only option left in end stage liver disease is liver transplantation, although this is only available for a very limited group of patients.
Adenocarcinomas make up 95 percent of all colorectal cancer cases. In the gastrointestinal tract, adenocarcinomas develop in the cells of the lining inside the colon and/or the rectum. They typically start as a growth of tissue called a polyp. A particular type of polyp, called an adenoma, may develop into cancer. Polyps are often removed during a routine colonoscopy before they may develop into cancer.
In the mesenchymal subtype colon epithelial tumors, the PDGF-ß-receptor is typically over-expressed by stromal cells of mesenchymal origin. Tumor cells may also acquire PDGF-ß-receptor expression following epithelial-to-mesenchymal transition, which occurs during metastasis formation.
PDGF-ß-receptor expression in primary colon cancer is correlated with short disease-free and overall survival and the receptor likely contributes to the aggressive phenotype of colorectal tumors.