Topic 14 Leukocyte Migration and Inflamation

Introduction

In this lesson we describe the response of tissue to irritation or injury; a response we call inflammation. The inflammatory response constitutes an important part of both innate and acquired immunity. It has evolved as a protective response against injury and infection. Although in certain cases, such as hypersensitivity, inflammation becomes the problem rather than the solution to problem. With infection, by and large the inflammatory response is protective: it is one of the major responses to injury and constitutes a process aimed at bringing the injured tissue back to its normal state.

Most of the cells involved in the inflammatory response are phagocyte cells, first consisting mainly of the polymorphonuclear leukocytes , which are then followed by mononuclear cells, which include macrophages and lymphocytes. Lymphocytes circulate continually in the blood and lymph and also migrate into the tissues at sites of infection or tissue injury. This recirculation not only increases the chances that lymphocytes specific for a particular antigen will encounter that antigen but also is critical to the development of an inflammatory response. This lesson will cover the molecules and processes that play a role in leukocyte migration, various molecules that mediate inflammation, and the characteristic physiologic changes that accompany inflammatory responses.

Objectives

On completion of this section and the required reading, you should be able to:

n describe lymphocyte recirculation

n describe four classes of cell adhesion molecules

n describe four sequential but overlapping steps in neutrophil extravasation;

n discuss the role of G proteins in neutrophil extravasation;

n describe the location, structure and function of High endothelial venules;

n distinguish between neutrophilic and lymphocytic extravasation;

n construct a table to compare the C-C subgroup of chemokines with the C-X-C subgroup of chemokines;

n differentiate between the cyclooxygenase and lipoxygenase pathways of mediator production;

n describe the inflammatory process;

n compare the localized acute inflammatory response with the systemic acute phase response;

n draw a diagram to give an overview of the cells and mediators involved in a local acute inflammatory response;

n draw a diagram to give an overview of the cells and mediators involved in a systemic acute inflammatory response;

n describe the chronic inflammatory response;

n list 5 chronic inflammatory diseases associated with HEV;

n discuss the use of anti inflammatory agents to reduce long term inflammatory responses in infections, transplants and burns.

Required Reading

Please refer to the textbook key for specific readings for this section.

P Key Words

• Inflammation • extravasation • cell adhesion molecules (CAMs) • selectin • integrin • Leukocyte adhesion deficiency (LAD) • mucin, • chemoattractants • chemokines • G proteins • High endothelial venules (HEV) • trafficking or homing of lymphocytes • naive lymphocytes • effector lymphocytes • kinins • fibrin clot

• plasmin • complement • arachidonic acid • prostaglandins • cyclooxygenase pathway • lipoxygenase pathway • leukotriense • Slow reacting substances of anaphylaxis (SRS-A) • respiratory burst • chemotaxis, • opsonization • vasodilation • acute phase proteins • fibrosis • granuloma • multinucleated giant cells • corticosteroids

P Key Concepts

n Lymphocytes undergo constant recirculation between the blood, lymph, lymphoid organs, and tertiary extralymphoid tissues.

n Migration of leukocytes into inflamed tissue or lymphoid organs requires interaction between cell-adhesion molecules (CAMs) on the vascular endothelium and those on the circulation cells.

n Several types of mediators play a role in the inflammatory response

n Acute inflammation is a rapid response to injury that results in the accumulation of immunoglobulins and cells within tissues. It is a protective response. The cardinal signs of acute inflammation are heat, redness, swelling, pain, and loss of function. These may all be attributed to increased vascular permeability.

n Chronic inflammation is a response to prolonged injury or tissue damage. It may result in mononuclear cell infiltration of tissues and the deposition of large quantities of collagen

DID YOU KNOW?

Chronic inflamation of asthma in its severe form is difficult to treat because antihistamines are ineffective in treating this disease. Alternative approaches include corticosteroids. In addition and new generation of experimental drugs may in the future offer added alternatives for chronic inflamation of asthma sufferers:

At the moment the approved anti-inflammatory agents include corticosteroids and nonsteroidal drugs. Of these, the steroid are the most potent. Until about a decade ago, patients generally took the steroids orally, and the side effects (such as weight gain, osteoporosis and ulcers) posed a major problem More recently many studies have shown that the inhaled, or topically administered, versions can achieve good control without producing significant unwelcome effects. On the other hand, inhaled steroids may not attain full effectiveness in people who undergo very frequent asthmatic attacks or who have perpetual breathing difficulties.

This last problem has spurred a search for anti-inflammatory agents that are more potent than corticosteroids but also relatively nontoxic. Two of the more exciting classes of drug candidates aim to block the activity of inflammatory cytokines and the adhesion molecules that facilitate migration of immune system cells from the blood into tissue. In theory, such products should ameliorate not only asthma but many allergic disorders, including some that are not now amenable to treatment (such as chronic skin allergies). These drugs have not yet entered clinical trials for the treatment of asthma, but preliminary studies in humans and other primates are encouraging.

Research into experimental therapies for asthma does not end there. In addition to developing drugs that should block enzymes involved in signal transduction, pharmaceutical houses are devising new products that interfere with the activity of mediators made by mast cells and basophil. For instance, several companies are well into clinical trials of substances that block the functioning of leukotrienes. The drugs reduce symptoms and may work even better when combined with antihistamines.

Investigator also continue to explore the value of immunotherapy for asthmatics. This treatment is offered more often by allergists than pulmonary specialists. When such a disparity exists in medicine, it means that the treatment is not dramatically or completely effective in most patients.

Sadly, the incidence of asthma and the number of deaths it causes surged by more than 60 % in the 1980s. The reasons for the rises are mysterious, as is the explanation for why Americans of African descent are three times more likely than those of European descent to die from the disease.

L.M. Lichtenstein. Allergy and the Immune System. In: Life, Death and The Immune System, Scientific American, Special Issue, W. H. Freeman and Company, New York, 1994

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 15. The answers with explanations

are available at the end of the textbook.

2. Multiple Choice Questions

1. Which of the following is an acute-phase protein?

A) C-reactive protein

B) fibronectin

C) albumin

D) interleukin

E) interleukin-1

2. Which of the following is not one of the cardinal signs of inflammation?

A) heat

B) redness

C) pain

D) swelling

E) pus

3. Inflammatory stimuli cause the expression of which molecules on entodthelial cells?

A) lectins

B) cadherins

C) Fc receptors

D) selectins

E) acute-phase proteins

4. The metabolism of the long-chain unsaturated fatty acid arachidonic acid through the actions of lipoxygenases generates:

A) prostaglandins

B) thromboxanes

C) interleukins

D) leukotrienes

E) phospholipases

3. Definitions/Short Answer Questions

1. If fever is such a good thing, who do we usually try to reduce it when we are ill?

2. List and compare the differences between acute and chronic inflammation.

3. What may be the consequence of an absolute deficiency of interleukin-1.

4. What benefits may the acute-phase response confer on an individual. Are there any apparent disadvantages to this response?

5. Briefly discuss the major families of cell-adhesion molecules.

6. Explain the mechanism of action of salicylate, found in aspirin.

Where to Go from Here

Once you have completed the review, take some time and complete the objectives. If you are having trouble with any of the concepts, contact your instructor.

When you are confident that you can complete the objectives, proceed to the next topic.