Chronic Inflammatory Processes
There are seven-day wars and there are hundred-day wars, and having experienced both we can tell you that there is definitely a difference. The common factor is that there is conflict even though the “style” changes. When does the acute short-term blitz become a long drawn-out conflict? That’s s what this chapter is all about. A lot of shells have gone over the trench since we began exploring the defensive system of inflammation, so we would like to do a quick review of some of the essential aspects. Please turn to the Introduction (page ix) and review the basic types of inflammatory reactions. Once you have done that, come right back here (we are waiting, and the clock is ticking… ).
Why did we insert this chapter after the chapters on the immune system and hypersensitivity? Because chronic inflammation involves the immune system and immunologic responses. The cell that orchestrates most chronic inflammatory reactions is the CD4+ T cell. Without knowledge of the immune system, chronic inflammation would be unfathomable.
It is important to point out that there is no clear dividing line between acute and chronic inflammation. If the cause of the initial injury is not completely eliminated, acute inflammation will gradually give way to chronic inflammation, but there is no set time sequence.
How do you know a chronic situation when you see it?
Whereas acute inflammation involves exudative reactions, in which fluid, plasma proteins, and cells leave the bloodstream and enter the tissues, chronic inflammation is characterized by infiltration of injured tissue by leukocytes, as well as by proliferative responses, where cells are stimulated to multiply.
Interestingly, a majority of the most crippling diseases of humans involves chronic rather than acute inflammatory reactions. Leprosy, rheumatoid arthritis, tuberculosis, chronic pyelonephritis, syphilis, liver cirrhosis, and periodontal disease are all examples of chronic inflammatory diseases.
When we said there is a difference in “style” we meant that tissue damage frequently begins “quietly” as a low-grade, smoldering response that becomes apparent only after much damage has been inflicted on the tissue.
Chronic inflammation may develop in two ways, depending on the nature of the inflammatory stimulus or stimuli involved:
- It may supersede an acute inflammatory response that is not completely resolved. This occurs when the inflammatory response is unable to eliminate the injurious agent.
- It may develop in the absence of an antecedent acute response. This is the case when the immune system responds to a foreign antigen. Or, this may occur when the infectious agent is of low toxicity as compared with agents that are capable of initiating an acute inflammatory response.
The term chronic denotes an inflammatory response that persists for more than a few days or weeks. A chronic inflammatory response is characterized by a proliferation of:
- Vascular elements,
and an infiltration of “round cells” (also referred to as “mononuclear cells”). These are:
- Plasma cells (sometimes)
Collectively, these elements comprise chronic inflammatory tissue. In chronic inflammation, macrophages and lymphocytes may at times be the first cells to respond. (In an acute response you would expect neutrophils first.) In fact, the T-helper cell and the macrophage are the key cells in initiating a chronic inflammatory response.
Chronic inflammation is basically an immune response initiated in response to persistent antigen.
In chronic inflammation, the number of neutrophils is reduced relative to the number of mononuclear cells. (Why do neutrophils predominate in acute inflammation? What attracts them to a site of injury? We know you are growing weary, but if you can’t t handle these questions you had better review chapter 2—we won’t t tell anyone!)
Chronic inflammation is often associated with irreversible destruction of normal parenchyma. Fibrous connective tissue then fills the resultant defects. A good example of this is liver cirrhosis, where hepatic lobules are replaced by collagen fibers (Fig 7-1).
What occurs is a seesaw process of destructive mechanisms (inflammatory-degenerative) and healing (scar tissue), the end result of which may be permanent loss of function in the affected parts of the body.
Clinically, pain is often minimal or absent. Chronic inflammation may go unnoticed by the patient until it is too late to save the affected organ or organs. Thus, it lacks the warning signals that are so prominent in acute inflammation—swelling, heat, redness, and pain.
There, now you have all the general considerations. Proceed only if you hunger for juicy details. But, before we launch into details, you should remember that there is no clear boundary between acute and chronic inflammation (except in our chapters, of course). You can see that this may be so because such things as infectious agents, foreign bodies, chemicals, and immunologic factors may each produce inflammatory reactions, acute and chronic. Consequently, one could expect to see a great deal of overlap between acute and chronic responses.
Can he acute inflammatory process become chronic?
The answer is yes!
As an example, let’s use the chronic abscess. Suppurative infections involve bacteria that collectively are referred to as pyogenic, or pus-producing, organisms. Pyogenic bacteria include staphylococci, many gram-negative bacilli, meningococci, pneumococci, and gonococci. When these organisms infect the skin or a solid organ, they produce an abscess. An abscess is a localized accumulation of pus consisting of dead leukocytes (predominantly neutrophils), inflammatory exudate, and necrotic tissue.
Basically, pyogenic bacteria evoke a massive emigration of neutrophils. In order for pus to form, the bacteria must be resistant to phagocytosis and killing, thus ensuring a continuing emigration of neutrophils.
The designation, chronic abscess, is based entirely on temporal considerations. If an abscess persists for more than a few days it becomes a chronic lesion. With time, the abscess cavity containing pus is walled off by chronic inflammatory tissue that has formed around it.
The wall around the abscess is called a pyogenic membrane. Collagen fibers are oriented around the periphery of the lesion, forming a sort of capsule. In addition to fibroblasts and endothelial cells, variable numbers of lymphocytes and macrophages are found within the pyogenic membrane. Thus, the immune system creates a wall around the area of suppuration in an attempt to keep it localized and to provide support for the neutrophils (eg, opsonizing antibodies, cytokines, etc). There is a close relationship between the chronic inflammatory response and repair. This will become clear when you study the chapter on repair.
Actually, chronic inflammation can be thought of as “frustrated repair.” Repair is thwarted because it is held in abeyance by the presence of irritants. Complete removal of the irritants is essential for repair to progress to completion.
Everything that is needed for repair is present in chronic inflammatory tissue, that is, fibroblasts, small blood vessels, and macrophages (for wound debridement). In fact, repair is occurring all the time in chronic inflammation (remember the seesaw between destruction and repair).
Relationship between immune hypersensitivity and chronic inflammation
In some cases, hypersensitivity may be the cause of chronic lesions. Examples of these are rheumatoid arthritis, systemic lupus erythematosus, and allergic contact dermatitis. In other conditions, hypersensitivity develops as a secondary response that is activated during the course of a disease process. Examples of this are tuberculosis and leprosy.
Both immediate and delayed types of hypersensitivity may develop in chronic inflammation.
- Whereas acute inflammation involves exudative reactions, chronic inflammation is associated with _____________ responses.
- In chronic inflammation, how does scarring occur?
- When does acute inflammation stop and chronic inflammation begin?
- Why is there a close relationship between chronic inflammation and repair?
- Chronic inflammation is a seesaw process involving cycles of _____________ and _____________.
- Why does chronic inflammation often go unnoticed?
- What is the histologic pattern of the chronic inflammatory response?
- How can a chronic abscess be recognized histologically?
- Which cells of the immune system orchestrate chronic inflammatory reactions?
Answers on page 219.
Causes of chroni inflammation
The basic cause of chronic inflammation is the persistence of etiologic factors that are difficult for the body to eliminate. Several major groups of causative agents are recognized.
Extracellular organisms primarily evoke an acute inflammatory response in which the neutrophil is the predominant inflammatory cell. However, when infectious agents are persistent and the acute inflammatory process cannot be resolved, chronic inflammation supersedes acute inflammation.
As we pointed out, chronic inflammation may develop either in the absence of acute inflammation or with only a brief initial acute inflammatory response. This is likely to be the case when the infectious agent is of low toxicity as compared with organisms that are capable of initiating an acute inflammatory response. Examples of low toxicity organisms include intracellular organisms such as Treponema pallidum, Mycobacterium tuberculosis/>