Although neutrophils are essential to host defence, they have also been implicated in the pathology of many chronic inflammatory conditions and ischemia-reperfussion injury. Hydrolytic enzymes of neutrophil origin and oxidatively inactivated protease inhibitors can be detected in fluid isolated from inflammatory sites. Under normal conditions, neutrophils can migrate to sites of infection without damage host tissues. This damage may occur through several independent mechanisms. These include premature activation during migration, extracellular release of toxic products during the killing of some microbes, removal of infected or damage host cells and debris as a first step in tissue remodeling, or failure to terminate acute inflammatory responses.
Ischemia-reperfusion injury is associated with an influx of neutrophils into the affected tissue and subsequent activation. This may be triggered by substances released from damaged host cells or as a consequence of superoxide generation through xantine oxidase.
Under normal conditions, blood may contain a mixture of normal, primed, activated and spent neutrophils. In the inflammatory site, mainly activated and spent neutrophils are present. Activated neutrophils have enhanced production of reactive oxygen intermediates (ROI). A subpopulation of neutrophils with the anhanced respiratory burst has been detected in the blood of people with an acute bacterial infection and patients with the adult respiratory distress syndrome (ARDS). This is a good example of the neutrophil paradox. Neutrophils have been implicated in the pathology of this condition because of the large influx of these cells into the lung and the associated tissue damage caused by oxidants and hydrolytic enzymes released from activated neutrophils. The impairment of neutrophil microbicidal activity that occurs as the ARDS worsens may be a protective response on the part of the host, which is induced locally by inflammatory products. This ''down-regulation'' of neutrophil function may explain why many of these patients eventually die from overwhelming pulmonary infections.
The acute phase of thermal injury is also associated with neutrophil activation, and this is followed by a general impairment in various neutrophil functions. Activation of neutrophils by immune complexes in synovial fluid contributes to the pathology of rheumatoid arthritis. Chronic activation of neutrophils may also initiate tumour development because some ROI generated by neutrophils damage DNA and proteases promote tumour cell migration.
In patient suffering from severe burns, a strong correlation has been established between the onset of bacteremic infection and reduction in the proportion and absolute numbers of neutrophils positive for antibody and complement receptors.
Oxidants of neutrophil origin have also been shown to oxidize low-density lipoproteins (LDL) which are then more effectively bound to the plasma membrane of macrophages through specific scavenger receptors. Uptake of these oxidized LDL by macrophages is thought to initiate atherosclerosis.
In addition, primed neutrophils have been found in people with
essential hypertension, Hodgkin's disease, inflammatory bowel
disease, psoriasis, sarcoidosis, and septicaemia, where priming
correlates with high concentrations
of circulating TNF-
(cachectin).
Hydrolytic damage to host tissue and therefore chronic
inflammatory conditions may occur only when antioxidant and
antiprotease screens are overwhelmed. Antiprotease deficiency is
thought to be responsible for the pathology of emphysema.
Many antiproteases are members of the serine protease inhibitor
(SERPIN) family. Although the circulation is rich in
antiproteases, these large proteins may be selectively excluded at
sites of inflammation because neutrophils adhere hightly to their
targets. Oxidative stress may initate tissue damage by reducing
the concentration of extracellular antiproteases to below the
level required to inhibit released proteases. Chlorinated oxidants
and 
can inactivate antiproteases
such as 
-protease
inhibitor and 
-macroglobulin
(which are endogenous inhibitors of
elastase) but, surprisingly, simultaneously activate latent
metalloproteases such as collagenases and gelatinase, which
contribute to the further inactivation of antiproteases.
Cytoplasmic constituents of neutrophils may also be a cause of
formation of specific
anti-neutrophil cytoplasmic antibodies
(ANCA) which are closely related to the development of systemic
vasculitis and glomerulonephritis. ANCA are antibodies directed
against enzymes that are found mainly within the azurophil or
primary granules of neutrophils. There are three types of ANCA
that can be distinguished by the patterns they produce by indirect
immunofluorescence when tested on normal ethanol-fixed
neutrophils. Diffuse fine granular cytoplasmic fluorescence (
cANCA) is typically found in Wegener's granulomatosis, in
some cases of microscopic polyarteritis and Churg
Strauss syndrome, and in some cases of crescentic and
segmental necrotising glomerulonephritis, but is rare in other
conditions. The target antigen is usually proteinase 3.
Perinuclear fluorescence (
pANCA) is found in many cases of
microscopic polyarteritis and glomerulonephritis. These antibodies
are often directed against myeloperoxidase but other targets
include elastase, cathepsin G, lactoferrin, lysozyme and
-D-glucuronidase.
The third group designated
''atypical''
ANCA includes neutrophil nuclear fluorescence and some unusual
cytoplasmic patterns and while a few of the target antigens are
shared with pANCA, the others have not been identified yet.
pANCA are also found in a third of patients with Crohn's disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.