Fibrosis, the formation of excessive amounts of fibrotic or scar tissue, is a central issue in medicine. Scar tissue blocks arteries, immobilizes joints and damages internal organs, wreaking havoc on the body's ability to maintain vital functions. Every year, about 1.3 million people are hospitalized due to the damaging effects of fibrosis, yet doctors have few therapeutics to help them control this dangerous condition. Fibrosis can follow surgery in the form of adhesions, keloid tumors or hypertrophic (very severe) scarring. Fibrosis causes contractures and joint dislocation following severe burns, wounds or orthopedic injuries; it can occur in any organ and accompanies many disease states, such as hepatitis (liver cirrhosis), hypertension (heart failure), tuberculosis (pulmonary fibrosis), scleroderma (fibrotic skin and internal organs), diabetes (nephropathy) and atherosclerosis (fibrotic blood vessels). Ironically, the very process designed to repair the body can lead to dangerous complications. Like epoxy, scar tissue serves only a structural role. It fills in the gaps, but cannot contribute to the function of the organ in which it appears. For example, as fibrotic scar tissue replaces heart muscle damaged by hypertension, the heart becomes less elastic and thus less able to do its job. Similarly, pulmonary fibrosis causes the lungs to stiffen and decrease in size, a condition that can become life-threatening. Fibrotic growth can also proliferate and invade the healthy tissue that surrounds it even after the original injury heals. Too much scar tissue thus causes physiological roadblocks that disfigure, cripple or kill.
In most cases, fibrosis is a reactive process, and several different factors can apparently modulate the pathways leading to tissue fibrosis. Such factors include the early inflammatory responses, local increase in fibroblast cell populations, modulation of the synthetic function of fibroblasts, and altered regulation of the biosynthesis and degradation of collagen.
One of the most important pathologies for which fibrosis is a problematic factor is cardiac surgery. The number of patients undergoing cardiac surgery has been steadily increasing, and as a consequence, the number of cardiac reoperations has also increased..sup.1-6 It has been estimated that one out of every five patients undergoing coronary artery bypass surgery will require a reoperation..sup.3,4 Reoperative cardiac surgical procedures are associated with a significantly greater complication rate than that of the initial procedure..sup.5,6 For example, the post-operative complication rate following a reoperative coronary artery bypass procedure nearly doubles..sup.6 As a consequence, cardiac reoperations are associated with increased morbidity and mortality..sup.2-6 An important contributory factor for the increased complications with cardiac reoperations is the adhesions which form secondarily from the initial entry into the pericardium..sup.1-6 These fibrous adhesions begin to form immediately following the surgical procedure and consist of collagen and other extra cellular proteins..sup.7-9 It has been demonstrated in a number of cell systems that enhanced collagen synthesis can occur due to increased production of angiotensin II (Ang II) and subsequent activation of the Ang AT.sub.1 receptors..sup.10,11 Moreover, increased production of Ang II has been directly demonstrated in fibrotic pericardium..sup.12 The post-operative period following cardiac surgery is associated with heightened neurohormonal stimulation, which in turn could potentially contribute to pericardial adhesion formation..sup.13
The increased production of Ang II is due to the activation of the body's reninangiotensin-aldosterone system (RAAS). The enzyme cascade of the renin-angiotensin system (RAS) comprises a series of biochemical sequences. Angiotensinogen, a .alpha.2-macroglycoprotein, is split by the renin enzyme into the deca-peptide angiotensin I, which itself is biologically only very weakly active. The next step in the cascade is the removal of a further two amino acids by the action of the angiotensin-converting enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin II.
Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes which are termed e.g. AT.sub.1 - and AT.sub.2 -receptors. Great efforts have been made lately to identify substances that bind to AT.sub.1 -receptors. Such active ingredient(s)s are often termed angiotensin II antagonists. Because of the inhibition of the AT.sub.1 -receptor such antagonists can be used e.g. as antihypertensives or for the treatment of congestive heart failure.
The work of Brilla and Weber.sup.21 report experiments in vitro, which clearly show the involvement of the AT.sub.1 and AT.sub.2 Ang receptors in the pathological effect of Ang II especially on fibroblasts because of collagen deposition and fibrotic lesions. These reports concluded that AT.sub.1 receptor blockade may be valuable in preventing myocardial fibrosis or renal disease progression.
Many procedures have been attempted to treat fibrosis such as is disclosed in U.S. Pat. No. 5,645,839 issued to Chobanian on Jul. 8, 1997. The focus of this patent is the combined use of angiotensin inhibitors and nitric oxide stimulators for the treatment of myocardial fibrosis. This patent is directed to the concept that inhibition of angiotensin II production and enhanced nitric oxide production will reduce cardiovascular fibrosis. Cardiovascular fibrosis is defined as abnormal deposition of scar tissue due to naturally occurring disease processes such as myocardial fibrosis secondary to hypertension, arterial fibrosis due to arteriosclerosis, pulmonary fibrosis and scleroderma. Further, U.S. Pat. No. 5,529,992 issued to Weber on Jun. 25, 1996 discloses a method of using an aldosterone antagonist such as spironolactone, at a dosage which does not disrupt a patient's normal electrolyte and water-retention balance, to inhibit myocardial fibrosis, including left ventricular hypertrophy (LVH). U.S. Pat. No. 5,684,007 discloses a method for inhibiting cardiac fibroblast growth using a carbostyril derivative. This method is only demonstrated on cardiac cells in vitro. However, none of the known treatments are concerned with preventing fibrosis and the formation of adherences following surgery.
Due to the extreme debilitating effects of fibrosis, there is a need for a method to reduce surgical fibrosis and adhesion formation.
There is also a need for of a method for reducing pericardial fibrosis and adhesion formation following cardiac surgery.
Further, there is a need of a method for reducing fibrosis which results from induced pathological conditions in a patient.
There is also a need for a pharmaceutical composition comprising AT.sub.1 receptor antagonists or a pharmaceutically acceptable salt thereof for reducing surgical fibrosis and adhesion formation.