inflammation, acute inflammation

1. Ikram Ullah
M.Phil MLSc

2. Overview of Inflammation
 The survival of all organisms requires that they
eliminate foreign invaders, such as infectious agents,
and damaged tissues
 These functions are mediated by a complex host
response called inflammation
 Inflammation is a protective response involving host
cells, blood vessels, and proteins and other mediators
that is intended to eliminate the initial cause of cell
injury, as well as the necrotic cells and tissues resulting
from the original insult, and to initiate the process of
repair

3.  Inflammation accomplishes its protective mission by first
diluting, destroying, or otherwise neutralizing harmful
agents (e.g., microbes, toxins)
 It then sets into motion the events that eventually heal and
repair the sites of injury.
 Without inflammation, infections would go unchecked
and wounds would never heal
 The cells and molecules of host defense, including
leukocytes and plasma proteins, normally circulate in the
blood, and the goal of the inflammatory reaction is to bring
them to the site of infection or tissue damage.
 In addition, resident cells of vascular walls and the cells
and proteins of the extracellular matrix (ECM) are also
involved in inflammation and repair (Fig. 2–1)

5.  Inflammation can be acute or chronic
 Acute inflammation is rapid in onset and of short
duration, lasting from a few minutes to as long as a few
days, and is characterized by fluid and plasma protein
exudation and a predominantly neutrophilic leukocyte
accumulation
 Chronic inflammation may be more insidious, is of
longer duration (days to years), and is typified by
influx of lymphocytes and macrophages with
associated vascular proliferation and fibrosis
(scarring).

6.  Inflammation is induced by chemical mediators that
are produced by host cells in response to injurious
stimuli

7.  When a microbe enters a tissue or the tissue is injured, the
presence of the infection or damage is sensed by resident
cells, mainly macrophages, but also dendritic cells, mast
cells, and other cell types
 These cells secrete molecules (cytokines and other
mediators) that induce and regulate the subsequent
inflammatory response
 Some of these mediators promote the efflux of plasma and
the recruitment of circulating leukocytes to the site where
the offending agent is located
 The recruited leukocytes are activated and they try to
remove the offending agent by phagocytosis

8. Cardinal Signs
 The external manifestations of inflammation, often called its
cardinal signs, are
 heat (calor), redness (rubor), swelling (tumor), pain (dolor), and
loss of function (functio laesa)
 These manifestations occur as consequences of the vascular
changes and leukocyte recruitment and activation,
 Inflammation is normally controlled and self-limited
 The mediators and cells are activated only in response to the
injurious stimulus and are short-lived, and they are degraded or
become inactive as the injurious agent is eliminated

9.  In addition, various anti-inflammatory mechanisms
become active.
 If the injurious agent cannot be quickly eliminated,
the result may be chronic inflammation, which can
have serious pathologic consequences

11. ACUTE INFLAMMATION
 The acute inflammatory response rapidly delivers
leukocytes and plasma proteins to sites of injury
 Once there, leukocytes clear the invaders and begin
the process of digesting and getting rid of necrotic
tissues
 Acute inflammation has two major components (Fig.
2–2):

12.  Vascular changes: alterations in vessel caliber resulting in
increased blood flow (vasodilation) and changes in the
vessel wall that permit plasma proteins to leave the
circulation (increased vascular permeability)
 In addition, endothelial cells are activated, resulting in
increased adhesion of leukocytes and migration of the
leukocytes through the vessel wall
 Cellular events: emigration of the leukocytes from the
circulation and accumulation in the focus of injury
(cellular recruitment), followed by activation of the
leukocytes,
 Enabling them to eliminate the offending agent.
 The principal leukocytes in acute inflammation are
neutrophils (polymorphonuclear leukocytes)

14. Stimuli for Acute Inflammation
 Infections (bacterial, viral, fungal, parasitic)
 Trauma and various physical and chemical agents (e.g.,
thermal injury, such as burns or frostbite; irradiation;
toxicity
 Tissue necrosis (from any cause), including ischemia and
physical and chemical injury
 Foreign bodies (splinters, dirt, sutures, crystal deposits)
 Immune reactions (also called hypersensitivity reactions)
against environmental substances or against “self” tissues.

15. Recognition of Microbes, Necrotic Cells,
and Foreign Substances
 It was postulated that microbes and dead cells must elicit
some sort of “danger signals” that distinguish them from
normal tissues and mobilize the host response
 It is now established that phagocytes, dendritic cells and
many other cells, such as epithelial cells, express receptors
that are designed to sense the presence of infectious
pathogens and substances released from dead cells
 These receptors have been called “pattern recognition
receptors” because they recognize structures (i.e.,
molecular patterns) that are common to many microbes or
to dead cells

16.  Toll-like receptors (TLRs): are microbial sensors which
recognize products of bacteria (such as endotoxin and
bacterial DNA), viruses (such as double stranded
RNA), and other pathogens (Fig. 2–3, A)
 TLRs are located in plasma membranes and
endosomes, so they are able to detect extracellular and
ingested microbes
 TLRs and the other receptors recognize products of
different types of microbes and thus provide defense
against essentially all classes of infectious pathogens

17.  Recognition of microbes by these receptors activates
transcription factors that stimulate the production of a
number of secreted and membrane proteins
 These proteins include mediators of inflammation,
antiviral cytokines (interferons), and proteins that
promote lymphocyte activation and even more potent
immune responses

19. Vascular Changes
 The main vascular reactions of acute inflammation are
increased blood flow secondary to vasodilation and
increased vascular permeability, both designed to bring
blood cells and proteins to sites of infection or injury

20. Changes in Vascular Caliber and Flow
 After transient vasoconstriction (lasting only for seconds),
arteriolar vasodilation occurs, resulting in locally increased
blood flow and engorgement of the down-stream capillary
beds
 This vascular expansion is the cause of the redness
(erythema) and warmth characteristic of acute
inflammation
 The microvasculature becomes more permeable, and
protein-rich fluid moves into the extravascular tissues
 This causes the red cells in the flowing blood to become
more concentrated,

21.  Thereby increasing blood viscosity and slowing the
circulation (stasis)
 As stasis develops, leukocytes (principally neutrophils)
begin to accumulate along the vascular endothelial
surface—a process called margination
 Protein rich fluid accumulation is called an exudate.
 Exudates must be distinguished from transudates,
which are interstitial fluid accumulations caused by
increased hydrostatic pressure, usually a consequence
of reduced venous return

23. Cellular Events: Leukocyte Recruitment
and Activation
 Leukocyte Recruitment: Leukocytes normally flow
rapidly in the blood, and in inflammation, they have to
be stopped and brought to the offending the site of
tissue damage, which are typically outside the vessels
 (1) margination and rolling along the vessel wall;
 (2) firm adhesion to the endothelium;
 (3) transmigration between endothelial cells; and
 (4) migration in interstitial tissues toward a
chemotactic stimulus (Fig. 2–5).

25. Leukocyte Activation
 Phagocytosis of particles
 Intracellular destruction of phagocytosed microbes and dead cells
by substances produced in phagosomes
 Liberation of substances that destroy extracellular microbes and
dead tissues,
 A recently discovered mechanism by which neutrophils destroy
extracellular microbes is the formation of extracellular “traps.”
 Production of mediators, including arachidonic acid metabolites
and cytokines, that amplify the inflammatory reaction, by
recruiting and activating more leukocytes