Cytokines and Lung inflammation

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					               Cytokines and Lung inflammation
                Stephan F van Eeden, Division of Internal Medicine,
           University of British Columbia, Pulmonary Research Laboratory,
                                 Vancouver, BC, Canada

        Cytokines are low-molecular-weight soluble proteins (generally <30 kda)
that transmit signals between cells. Cytokines are produced by epithelial and
mesenchymal cells which amplify inflammatory responses in the lungs and other
organs. Cytokines are produced in “cascades” in which the initial cytokine
signals are amplified many-fold by target cells, such as epithelial cells,
fibroblasts, and endothelial cells. Cytokines function in “networks” in which
feedback occurs at many points to coordinate and regulate cytokine and cellular
responses. Instead, it is now recognized that a balance of proinflammatory and
anti-inflammatory factors influences the net inflammatory response in the lungs.
        Experimental studies suggest that cytokine responses normally are
compartmentalized in the lungs, and that the study of blood specimens provides
an incomplete reflection of inflammatory events in the lungs. However,
compartmentalization is lost to some extent during severe inflammatory
responses resulting in a systemic inflammatory response. This systemic
response may further augment the local inflammatory response in the lung
resulting in a vicious cycle. Sampling cytokines in the lungs is difficult because
cytokines function not only in the alveolar compartment, where they may exist as
soluble constituents of alveolar fluids, but also in the tissue compartment, where
they bind to components of the extracellular matrix. Two approaches have been
used to measure cytokines in biological fluids: biological assays using responsive
target cells, and enzyme-linked immunosorbent assays using polyclonal or
monoclonal antibodies. Biological assays target cell lines and are often affected
by more than one cytokine.
        The hallmark lesion of acute lung injury or ARDS, described carefully by
Bachofen and Weibel, is widespread destruction of the alveolar epithelium and
flooding of the alveolar spaces with proteinaceous exudates containing large
numbers of neutrophils (polymorphonuclear leukocytes (PMNs).               Because
evidence linking PMNs and lung injury, and the critical involvement of cytokines
in the recruitment of PMNs into tissues, it was hoped that the study of cytokines
in BAL would provide clues about the mechanisms that regulate injury in the
lungs.     It is now recognized that a complex balance exists between
proinflammatory and anti-inflammatory cytokines, and that “cytokine balance” is a
key concept in understanding the biological activity of cytokines in biological
fluids.

Cytokines and the initiation and progression of acute lung injury:
TNF- and IL-1
       Interest in the roles of the early response cytokines TNF- and IL-1 was
stimulated by the recognition that these cytokines stimulate cytokine production
by lung epithelial and mesenchymal cells that do not respond directly to bacteria
and their products. Suter et al. found significant levels of TNF- in lung fluids of
patients at the onset of ARDS. The effects of TNF- are modulated by two TNF-
 receptors (TNFRI, p55, and TNFRII, p75) that are shed from the surface of
macrophages and other cells and that the ratios of TNF- to its receptors are
lowest on days 1 and 3 of ARDS. This suggests that the activity of TNF- is
effectively inhibited in the aqueous phase of lung fluids of patients with ARDS.
Like TNF-, IL-1 is present in BAL at the onset of ARDS. In patients with
sustained ARDS, the IL-1 concentration in BAL on day 7 correlates with
survival, with higher concentrations in patients who die. The observation that
very few molecules of IL-1 are needed to trigger target cells probably explains
why bioactive IL-1 is detectable in the proinflammatory assay, despite the
apparent excess of inhibitors over free IL-1.
Chemokines
        Leukocyte migration is directed to a large extent by chemokines. The two
major classes include the -chemokines, which recruit PMNs, and -chemokines,
which recruit monocytes and lymphocytes. IL-8, GRO, and ENA-78 are
detectable in the BAL of patients at risk for ARDS and during the course of
established ARDS. Alveolar macrophages are a major source of chemokines in
the airspaces, and produce IL-8, GRO-related peptides, and ENA-78. On a
quantitative basis, IL-8 is the most abundant product following LPS stimulation.
Other cells of the alveolar environment also produce - and -chemokines, but
do so in response to the proinflammatory cytokines TNF- and IL-1, and not
directly in response to bacterial products such as LPS.
        Correlations between IL-8 and total PMN in BAL, at the onset of ARDS are
poor and the relationship between IL-8 and PMN actually grows stronger with
time in patients with persistent ARDS. Concentrations of GRO and ENA-78
exceed the concentration of IL-8 in BAL throughout most of the course of ARDS.
Antibodies to IL-8 suggested that IL-8 was the dominant PMN chemoattractant in
the fluids studied. Chemokines in the aqueous phase of alveolar fluids are in
equilibrium with chemokines bound to tissue matrix. At present, there is no way
to estimate the size of the tissue-bound pool.

IL-6, IL-10, MIF:
        IL-6 is produced by activated macrophages and stimulates acute-phase
responses in the liver. IL-6 concentrations are very high in the BAL of patients at
risk for ARDS and that they remain elevated throughout the course of established
ARDS. IL-6R is an agonist rather than an antagonist. The concentration of
soluble IL-6R is elevated in the BAL of patients at risk, and throughout the course
of ARDS. Cellular reactions mediated by IL-6 should be highly favoured during
the course of ARDS.
        IL-10 is a counterregulatory cytokines that inhibits cytokine production by
stimulated macrophages. Low concentration of IL-10 favour cytokine production
in the alveolar environment. IL-10 treatment impairs bacterial clearance.
Donnelly et al. found that patients who died with ARDS had low concentrations of
IL-10 in BAL fluid at the onset of ARDS, suggesting inadequate dampening of
lung inflammatory responses.
       MIF is produced by several different types of cells, including cells of the
anterior pituitary gland, activated macrophages, and possibly the airway
epithelium and antagonizes the suppressive effects of cortisol on cytokine
production by alveolar macrophages. This suggests that MIF may act to sustain
inflammation in the alveolar spaces. The concentration of MIF increases in the
lungs of patients with sustained ARDS.



Cytokines and the recruitment of effector cells into the lung:
        Experimental studies have linked PMNs as one of the principle effector
cells that initiate and sustain acute lung injury. Miller et al. found that IL-8 in BAL
at the beginning of ARDS was highest in patients at risk for ARDS who later
developed ARDS. We have shown that IL-8 rapidly recruits PMNs from the bone
marrow. These PMN recruited from the marrow are younger and more immature.
Immature PMNs are larger and less deformable than their circulating
counterparts. Studies from our laboratory have shown that these immature PMNs
preferentially sequester in lung capillaries and are slow to migrate into the
inflammatory site. This suggests that these effector cells play an important role
in the pathogenesis of initiating and progression of acute lung injury. Other
important mediators that stimulate the bone marrow to release immature cells are
IL-6, and the hematopoietic growth factors such as GM-CSF and G-CSF.
Numerous cytokines can stimulate the marrow indirectly.
        Cytokines also modify the life span of leukocytes that migrate into tissue.
PMN accumulation in the lungs is a characteristic feature of acute lung injury.
Although PMNs typically have a short life span in tissue (24-72hrs), PMN survival
in the airspace is prolonged by leukocyte colony-stimulating factors such as GM-
CSF and G-CSF. Furthermore, immature cells release from the marrow have a
longer life span. The relationship between cytokine release, presence of
immature PMN in the inflammatory site and apoptosis of other cells in the
alveolar environment is uncertain.

Cytokines as predictors of severity of lung disease
       Using cytokines as a marker to predict subjects at risk to develop ARDS or
as a marker to predict outcome are still uncertain. Studies in several centres
have found that IL-8 does not predict outcome. IL-1 and MCP-1 are higher on
day 7 in patients who later die. Studies suggest that patients with persistent
elevation of BAL cytokines are more likely to have pulmonary dysfunction if they
survive. Cytokine measurements in BAL fluid of patients before and after the
onset of ARDS have provided valuable insights about the complexity of the
inflammatory response that occurs in the lungs.
No single cytokine predicts onset or outcome of disease and it is now recognized
that a balance of pro- and anti-inflammatory mediators influence the net
inflammatory response in the lung.
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