What are the rules?

1. How do I submit a question?
I will only accept questions submitted to: nsf.cowper.blog@gmail.com
2. Will all questions be answered?
No. As a very busy physician, researcher, and father, I will do my best to answer as many questions as I can, and to indicate where the answers come from. As this is a blog, please be aware that it will contain opinions, some of which may be mine alone.
3. Will the questioner's name be included in the post?
No. It is best from the medical privacy standpoint to post the questions anonymously.
4. Will you modify or make up the questions?
I will modify questions to suit the style of the page. I will create my own questions when I feel the urge to blog, but have no suitable questions on deck.
5. Will the answers ever change?
If new information becomes available that outdates a previous post, I will do what I can (within the limits of the software) to clarify this situation. Scientists are open minded, yet skeptical. They are evidence driven. If the evidence leads in a particular direction, that lead will be followed. If new knowledge develops and withstands the rigor of serious investigation, the answers must change.
6. Can I share this site with others?
Please feel free to encourage anybody with an interest in NSF to join in. However, please note, all posts on this blog are copyrighted by me, and cannot be shared or reproduced outside of this webpage without my personal written consent.

Shawn E. Cowper, MD

Monday, June 27, 2011

What is fibrosis?

Collagen is a protein made by animals and is the most abundant protein in mammals (1). It forms the structure, and provides the substance of skin, bone, and other connective tissues in humans. Collagen in human skin is chiefly of two types (Type I and Type III). Other types of collagen dominate in other organs and tissues. Collagen forms long strands or fibers, but is also capable of forming more elaborate shapes in different tissue types. Collagen production is normal and necessary for life. In human skin, collagen is chiefly formed by cells called "fibroblasts"(2).

If, for whatever reason, too much collagen is formed, the process is called "fibrosis"(3). One extreme version of fibrosis is "scarring" which occurs when fibrosis is extensive enough to obliterate the normal tissue architecture.

Fibrosis is can occur in many situations. In a myocardial infarction (heart attack) heart muscle cells will die due to the loss of available oxygen. To insure the integrity of the organ, collagen will form a scar. This is a trade off for the body. The heart can continue to function (saving the patient's life) yet will not function as well as it did originally.

In the event of traumatic injury to the skin, fibroblasts will create collagen to close the wound, knitting it together. Following surgery, an incision is sewn together, and the fibroblasts will "knit" together the edges of the cut. This occurs quickly. After a biopsy, stitches can usually be removed in a few days. The hole is closed, yet the fibroblasts continue to create new collagen to patch up the damage. After the structure is restored, fibroblasts and other cells will work to "remodel" the collagen, making it stronger, and insuring a closer semblance to the original tissue. This remodeling may occur over many weeks.

In the weeks following a large incision, the healing wound is red and tender around the stitches. This is because new blood vessels have formed and blood and inflammatory cells have made their way from these vessels into the surrounding tissues. These inflammatory cells coordinate the clean up of debris and the destruction of bacteria. They also summon local fibroblasts to migrate to the wound to create new collagen. Lastly, they send signals through the blood to recruit immature fibroblasts to come from the bone marrow. These immature fibroblast stem cells are called "fibrocytes." As they traverse the blood vessels to arrive at the site of injury they resemble white blood cells. They are called "circulating fibrocytes" (CFs). Once they arrive at the site of injury, they emerge from blood vessels into the tissues and transform from immature CFs to mature cells resembling fibroblasts.

CFs are present in everybody's blood at a low level. In some instances they may temporarily increase in number depending on the needs of the body. CFs can be identified in the blood by a combination of markers that "fingerprint" the cell. One of these is procollagen I (an immature form of Collagen type I). Another is a CD34. CD34 is a marker that identifies many types of "immature" cells, as well as the lining of blood vessels. The combination of CD34 and procollagen I in the same cell is unique to CFs (4).

The arrival of many CFs at the site of tissue injury leads to the production of abundant collagen. The incision scar will get very hard. Once the stitches are removed, the scar is raised and very firm. Over time, however, remodeling of this scar takes place, the amount of new collagen tapers off, and the scar flattens out and becomes flesh colored or slightly white.

There are many disorders that result in fibrosis. As with a heart attack, fibrosis may be the last point on a long journey that insures the continued function of an organism. Severe inflammation, such as one might see in pneumonia, can lead to lung fibrosis. Coal miner's lung, and asbestosis are examples of lung fibrosis that follow inhalation of small particles that cause continued, ongoing lung injury.

Skin fibrosis can also occur from many potential causes. In some disorders, the deposition of so much excess collagen can make the skin so stiff that joints cannot properly function. It is, as if, the skin has become as hard as a plaster or fiberglass cast. The joints may be normal, but if they cannot function due to this excess of collagen, in time they may become frozen in position.

Skin fibrosis due to diseases such as scleroderma (which means "hard skin"), morphea, scleromyxedema, and nephrogenic systemic fibrosis (NSF) all share an excess of skin collagen. Under the microscope, a pathologist may see excess fibroblasts and collagen, or they may simply see the collagen (without the fibroblasts). Pathologists describe the process as "fibrosis" when the fibroblasts are still visible, and "sclerosis" when only collagen is visible, and the fibroblasts have largely disappeared. This cannot be determined by clinical examination alone, and examining doctors such as dermatologists and rheumatologists may use the terms "fibrosis" and "sclerosis" synonymously. To a pathologist, they are very different, and serve the purpose of differentiating between several disorders.

To a pathologist, fibrosis is increased collagen and increased numbers of fibroblasts.