Page 304 - Williams Hematology ( PDFDrive )

279

CHAPTER 19 rather a nonspecific and salutary response to a variety of insults.
Through his microscopic examinations of transparent vital membrane
THE INFLAMMATORY preparations, German pathologist Julius Cohnheim concluded that
the inflammatory response is fundamentally a vascular phenomenon.
RESPONSE Phagocytosis was described late in the 19th century by Elie Metchnikoff
and his colleagues at the Pasteur Institute. Morphologic studies, using
both live animals and fixed histologic preparations, transformed our
understanding of inflammation and led to the currently held concepts
Jeffrey S. Warren and Peter A. Ward of inflammation-associated hemodynamic alterations, acute inflamma-
tion and chronic inflammation. During the past 5 decades, the modern
1,2
techniques of biochemistry, tissue culture, monoclonal antibody pro-
duction, recombinant DNA technology, and the genetic manipulation
SUMMARY of isolated cells and whole animals have enabled a more detailed under-
standing of the cellular and molecular mechanisms which underpin the
The acute inflammatory response is characterized by a rapid but relatively inflammatory response, the active resolution of inflammation, and the
short-lived localized increase in blood flow, an increase in microvascular transition to tissue repair and restitution. These studies, in concert with
permeability and the sequential recruitment of different types of leukocytes. “experiments of nature,” such as chronic granulomatous disease (Chap.
Acute inflammation may be followed by “chronic” inflammation and a super- 66) and the leukocyte adhesion deficiency disorders (Chap. 66), have
imposed series of reparative processes (e.g., angiogenesis, production of permitted the formulation of complex, yet elegant, models of acute and
extracellular matrix, parenchymal regeneration and scar formation). The early chronic inflammation and led to the promise of incisive therapeutic
hemodynamic changes at a site of inflammation establish low shear condi- approaches. A large array of human diseases is marked by either defects
tions that enable marginated leukocytes to engage in low-affinity selectin- in the development of the inflammatory response or the deleterious
mediated rolling interactions with activated endothelial cells. In response to effects of the inflammatory response itself.
locally produced soluble and cell surface mediators, endothelial cells and roll-
ing leukocytes sequentially express several sets of complementary adhesion GENERAL CHARACTERISTICS
molecules that include selectins, integrins, and members of the immunoglob-
ulin superfamily. Leukocyte and endothelial cell adhesion molecules mediate OF INFLAMMATION
the high-affinity adhesive interactions necessary for leukocyte emigration It is useful to consider inflammation as an acute or chronic (persistent)
from the vascular space along chemotactic gradients. Analogous, temporally process. Acute inflammation lasts from minutes to several days and is
regulated, soluble mediators and cellular adhesion molecules also orchestrate characterized by pronounced local hemodynamic and microvascu-
succeeding monocyte- and lymphocyte-rich chronic inflammatory responses. lar changes and leukocyte accumulation. The acute inflammatory
2,3
This paradigm is modulated by a vast network of surface-active and soluble response is consistently marked by microvascular leakage and the accu-
inflammatory mediators. Recruited leukocytes and cells indigenous to the mulation of neutrophils. The four cardinal signs of acute inflammation,
anatomic site of inflammation both play critical roles in host defense, resolu- alluded to above, can be accounted for within the physiologic param-
tion of inflammation and tissue repair. eters of inflammation. The systemic effects of inflammation, particu-
larly acute inflammation, account for the familiar clinical findings of
fever, acute-phase response and altered sensorium. In turn, sepsis is a
systemic inflammatory response syndrome that occurs in response to
HISTORY infection; severe sepsis is sepsis complicated by acute organ dysfunc-
tion; and septic shock is sepsis complicated by either fluid resuscitation-
The sentinel clinical features of acute inflammation—rubor, calor, resistant hypotension or by hyperlactatemia. 4
tumor, and dolor—have been recognized for at least 5000 years. The chronic inflammatory response, which lasts much longer and
1
Dr. John Hunter, the renowned late 18th-century Scottish surgeon, is more varied in its effects, is marked by growth of new capillaries
observed that the inflammatory response is not a disease per se but and proliferation of resident fibroblasts. Cellular infiltrates typically
2,3
include monocytes and lymphocytes, but there are many variations in
the cellular composition, anatomic distribution and tempo of develop-
Acronyms and Abbreviations: ADAM, a disintegrin and metalloproteinase; BPI, ment of chronic inflammatory lesions. Chronic inflammatory processes
bacterial permeability-increasing protein; CAP37, cationic antimicrobial protein; DARC, can be classified according to these variations. For example, granuloma-
Duffy antigen receptor for chemokines; CD, cluster of differentiation; eNOS, endothelial tous inflammation is a chronic process marked by nodular aggregates of
nitric oxide synthase; HEV, high-endothelial venule; HPETE, hydroperoxyeicosatetrae- mononuclear phagocytes that have become “transformed” into epithe-
noic acid; ICAM, intercellular adhesion molecule; IFN, interferon; Ig, immunoglobulin; lioid histiocytes, so-called because of their similar appearance to epi-
IL, interleukin; iNOS, inducible nitric oxide synthase; LT, leukotriene; LTB /C /D / thelial cells. Granulomas may be distributed along blood vessels (e.g.,
2
4
4
4
E , leukotriene B /C /D /E ; MadCAM, mucosal addressin cell adhesion molecule; angiocentric), along upper airways (e.g., bronchocentric), or randomly
4
4
4
4
4
MASP, mannan-binding lectin-associated serine protease; MBL, mannan-binding throughout the interstitium or parenchyma of an organ. Granulomas
lectin; NADPH, nicotinamide adenine dinucleotide phosphate (reduced); NO, nitric may vary morphologically. Tuberculous granulomas often contain areas
oxide; PAF, platelet-activating factor; PARs, proteinase-activated receptors; PNAd, of caseous necrosis while sarcoidosis-associated granulomas are often
2
peripheral node addressin; PSGL-1, P-selectin glycoprotein ligand-1; RGD, arginine- cellular and exhibit fibrosis but usually without areas of necrosis. Other
glycine-aspartic acid peptide sequence; TACE, tumor necrosis factor-α converting chronic inflammatory processes are marked by a preponderance of eos-
enzyme; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VLA, inophils or plasma cells. In contrast to the more stereotyped appearance
very-late antigen. of an acute inflammatory lesion, the particular appearance of a chronic
inflammatory lesion can sometimes provide insight into its cause (e.g.,
Kaushansky_chapter 19_p0279-0292.indd 279 9/17/15 5:51 PM