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Microsoft word - anti-inflammatory therapies.doc
ANTI-INFLAMMATORY THERAPY IN CYSTIC FIBROSIS
Mario Romano Department of Biomedical Sciences and Aging Research Center, “G. D’Annunzio” University Foundation, Chieti-Pescara, Italy The inflammatory response in Cystic Fibrosis
An exuberant and persistent acute inflammatory reaction is commonly observed in the lung from cystic fibrosis (CF) patients, representing a key pathogenetic event of lung damage and respiratory insufficiency. CF inflammation is characterized by massive infiltration of activated neutrophils and is sustained by over expression of a repertoire of pro-inflammatory mediators and receptors (1). The mechanisms responsible of lung inflammation in CF are still under debate. One line of evidence suggests that inflammation is triggered by bacterial infection, which develops early in life and is promoted by reduced bacterial clearance, due to mucous viscosity (2). More recent results indicate, instead, that CF airway is prone to inflammation, even in the absence of appreciable bacterial colonization (3). It appears that a dysfunctional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) may trigger over-production of pro-inflammatory cytokines by respiratory epithelial cells either at basal or in response to bacterial infection (4). In vitro studies have shown that inhibition of CFTR activity increases interleukin-8 (IL-8) secretion and NF-κB nuclear translocation in normal human respiratory epithelial cells (5). On the other side, CFTR may regulate functions of circulating cells involved in the immune-surveillance and in the inflammatory response. In particular, polymorphonuclear neutrophils (PMNs) express a functional CFTR protein, which regulates chlorination of bacterial proteins (6). Also, CFTR controls phagosome acidification and bacterial killing in alveolar macrophages (7).
It is becoming clear that, under physiological circumstances, the resolution of the
inflammatory response is a well timely-ordered, active process which involves the participation of a number of mediators (8). Thus, pathology may develop also because of alterations in the resolution phase of the inflammatory reaction. Indeed, it has been reported that a defect in generation of the endogenous pro-resolution lipid mediator lipoxin A4 (LXA4) can be observed in CF (9). In aggregate, these observations indicate
that a number of factors concur to maintain an acute inflammatory state in CF lung.
This article reviews the anti-inflammatory protocols employed in CF, with the
introduction of novel potential experimental approaches.
Classic anti-inflammatory drugs
Although steroids can improve lung function and retard parenchyma deterioration, their
use in CF has been undermined by the serious side-effects (cataracts, glucose intolerance,
hypertension and growth retardation) associated with long-term administration (10). To
minimize such effects, inhaled corticosteroids have been used for both short and long
term treatments. Unfortunately, clinical results with aerosolized steroids have been
modest (11). Recently, a novel strategy for steroid administration has been proposed.
Erythrocytes from patients are loaded with dexamethasone and then reinfused (12).
Preliminary data from a small number of patients indicate that erythrocyte-mediated
delivery of steroid is relatively safe and is associated with a statistically significant
improvement of FEV1 (12). Larger studies are however required to assess the real
efficacy of this treatment to control lung inflammation in CF.
High doses of ibuprofen, to reach plasma concentrations between 50 and 100 µg/ml, have
been administered to CF children for 4 years in a randomized double-blind trial (13).
Initial results showed a slower progression of lung disease in patients treated with
ibuprofen (13). A ten-year follow-up of this study showed the persistence of the
improvement in lung function in patients taking ibuprofen (14). Furthermore, children
with mild lung disease treated with ibuprofen had 33% less reduction in FEV1 compared
with children randomized to placebo (15). The risk of side effects (mainly GI bleeding)
and the need for an accurate monitoring of plasma concentrations may limit the use of
this drug, although benefits may prevail over the risks. The use of more selective
cyclooxygenase-2 (COX-2) inhibitors is not recommended because of their documented
cardiovascular side effects in long-term treatments (16). Alternative anti-inflammatory strategies
DNA released by apoptotic neutrophils infiltrating the CF airways, contributes to mucus
viscosity, which in turn promotes bacterial infection and exacerbation of respiratory
inflammation. Therefore, treatment with human recombinant deoxyribonuclease
(rhDNase) was proposed. 105 CF patients with normal lung function were randomized to
receive 2.5 mg/day of nebulizedi rhDNAse or no treatment for three years (17). Untreated
patients displayed over time an increase in the number of neutrophils as well as in
elastase activity and IL-8 levels in bronchoalveolar lavage fluids (BALF). Such
increments were not observed in BALF from patients treated with rhDNAse (17).
However, no significant variations in FEV1 were observed between untreated and
rhDNAse-treated patients. On the other hand, in a 96-week double-blind placebo-controlled randomized study involving a total of 474 CF patients, treatment with dornase alpha reduced the decay in lung functions and the risk of exacerbations (18). Similar
results emerged from the analysis of data from Epidemiologic Survey of Cystic Fibrosis
(19). Thus, rhDNAse may exert anti-inflammatory actions in CF patients with mild lung
disease, although the impact of this treatment on survival should be better evaluated in
longer follow up studies. Leukotriene receptor antogonists
Leukotrienes (LTs) are generated by 5-Lipoxygenase (LO)-catalyzed conversion of
arachidonic acid (20). They are potent regulators of the immune-inflammatory response.
In particular, LTB4, which is produced by PMNs and macrophages, is a potent
chemoattractant for PMNs (21). It activates specific membrane receptors belonging to the G-protein-coupled receptor (GPCR) family and denominated BLT1 and BLT2 (22).
Increased levels of LTB4 can be measured in epithelial lining fluid and exhaled breath
condensate from CF patients (23,24). Given that BLT1 plays a key role in the regulation
of PMN recruitment in the respiratory tract, contributing to inflammation progression (22), a multi center randomized, double blind, placebo-controlled phase II clinical trial with the BLT1 antagonist BIIL 284 BS was started. Unfortunately, this trial had to be
interrupted because of serious pulmonary adverse effects in patients taking the drug (25).
5-LO generates an additional class of leukotrienes termed cysteinyl leukotrienes
(Cys-LT), which regulate vascular tone and permeability and exert pro-inflammatory functions (26). CysLT activate two GPRC receptors, CysLT1 and CysLT2 (27). CysLT1
receptor antagonists are routinely used for treatment of allergic rhinitis and asthma (28). CysLT1 receptor antagonists have been administered also to CF patients. In one study,
montelukast was given to 11 clinically stable CF patients for two weeks (29). Patients displayed some improvement in exercise tolerance (29). In another study, montelukast was administered to 16 patients for three weeks (30). A reduction in levels of eosinophilic cationic protein levels and number of eosinophils was denoted, although functional tests remained unchanged (30). Improvement in respiratory parameters as well as decrease in cough, wheezing, levels of IL-8 and myeloperoxidase in sputum, was instead observed in other clinical investigation with montelukast in CF patients (31). Zafirlukast was also given to thirty CF patients with some improvement in clinical score (32).
Taken together, studies with CysLT1 inhibitors do not conclusively show a real
efficacy of this class of drugs as anti-inflammatory agents in CF. N-acethylcysteine
Oxidant stress may significantly contribute to progression of lung damage in CF.
Expression of genes regulating the redox/anti-oxidant systems was altered in the
CFTR∆F508 mice (33). N
-acethylcysteine is a sulfhydryl group donor with anti-oxidant
properties, which has been largely used as a mucolityc agent. In phase 1 clinical
investigation, high doses of N
-acethylcysteine (0.6 to 1.0 g three times per day) were
administered to 18 CF patients for four weeks (34). A significant reduction in sputum
elastase activity as well as neutrophil burden was observed, whereas no changes in
pulmonary functions were detected (34). A phase II trial is underway to determine
whether, by improving the neutrophil burden, N
-acethylcysteine can also ameliorate lung
function in the long-term.
Nitric oxide regulators
Generation of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS) is
impaired in CF respiratory epithelial cells (35). This contributes to enhance bacterial
infection and to exacerbate airway inflammation. Thus, drugs that increase NO
generation and/or bioavailability may be a useful tool to combat inflammation and
infection. In this respect, statins, which inhibit the 3-hydroxy-3-methylglutaryl-CoA
reductase pathway, restored iNOS expression in CF airway cells, with a mechanism
involving the Rho GTPase pathway (36). Statins may also regulate additional anti-
inflammatory mechanisms, namely inhibition of cytokine, chemokine production and of
chemokine receptor expression (37), NF-κB activation (38), MIP-1α expression in
monocytes (39), inhibition of PMN activation and recruitment (40). The impact of
simvastatin administration to CF patients is being currently evaluated.
On the other hand, NO formation may be increased by providing iNOS with L-Arginine,
which is enzymatically converted to NO. Administration of inhaled or oral L-Arginine to
CF patients resulted in increased NO formation, although a beneficial effect on FEV1
could not be observed (41).
Peroxisome proliferators-activated receptors (PPARs) represent a class of transcription
factors involved in the regulation of lipid metabolism and of the inflammatory response.
Among the three isoforms (α, β, γ) so far identified, PPAR-γ is highly expressed in the
respiratory epithelium as well as in alveolar macrophages (42). In addition, a decrease in
PPAR-γ expression was denoted in the lung from cftr--/-- mice compared to lung from
normal mice (43). Activation of PPAR-γ by endogenous (15-deoxy-∆12,14-prostaglandin
J2) or exogenous (thiozolidinediones) agonists results in down-regulation of pro-
inflammatory cytokine expression in airway cells (44) as well as in alveolar macrophages
(45). Thus, PPAR-γ activators have been proposed for treatment of chronic airway
inflammation (46). Together, these observations support the hypothesis that PPAR-γ
agonists may be beneficial in CF. A clinical trial with pioglitazone in CF patients in
Cytokines actively concur to the development and persistence of the inflammatory
reaction in CF. In particular, increased production of pro-inflammatory cytokines as well
as reduced formation of anti-inflammatory cytokines can be observed in CF patients.
Therefore, treatments aimed at regulating the cytokine network may be proposed for CF
therapy. In this respect, IL-10 plays a key role in the resolution of the inflammatory
response. Interestingly, IL-10 knockout mice display prolonged inflammation in response
to Pseudomonas aeruginosa
challenge (48). Moreover, treatment with IL-10 improved
survival of these mice (49). Therefore, administration of recombinant IL-10 could be a
therapeutic option for CF patients. On the other hand, interferon gamma (IFN-γ) can
modulate a number of mechanisms of inflammation and alterations in the IFN-γ pathway
have been detected in CF (50). Inhaled IFN-γ was administered to 66 patients randomized
to receive 500 or 1000 μg IFN-γ1b. Results from this study did not show changes in
inflammatory parameters or improvements in respiratory functions (51). Protease inhibitors
The massive infiltration of PMNs in CF airways is associated with the release of large
amounts of proteases stored in PMN granules. These proteases greatly contribute to the
development of inflammation and tissue damage. Thus, it has been proposed that
supplementation of the airway with anti-proteases may counter-balance the increment in
airway protease concentration which occur in CF. Early studies showed that inhaled α1-
antitrypsin suppressed neutrophil elastase in the airway lining fluid from 12 CF patients
(52). In a more recent prospective randomized investigation, 52 CF patients were given
25 mg inhaled α1-antitrypsin for four weeks (53). A reduction in pro-inflammatory
cytokines and PMNs in the induced sputum was observed, although there were no
changes in lung function (53). Aerosol preparation of engineered protein inhibitor human
neutrophil elastase (EPI-hNE4) revealed potent inhibitory capability of PMN elastase
(54). EPI-hNE4 protected rats from acute lung injury and reduced by 64% PMN influx in
rat airway after tracheal instillation of pooled sputum from children with CF (55). Phase
II clinical trials of engineered protein inhibitor human neutrophil elastase (EPI-hNE4),
which has been shown to efficiently reduce elastase concentrations as well as PMN
migration, are being carried out in Europe (47). Antibiotics
Anti- bacterial therapy may also decrease the inflammation burden in CF airway. A
number of evidence indicates that macrolides reduce formation of pro-inflammatory
cytokines in vitro and in vivo and also inhibit PMN migration and activation (56). In a
multicenter, double-blind, placebo-controlled trial, 87 CF patients were randomized to
oral azithromycin (250 or 500 mg) 3 days a week for 168 days, whereas 98 CF patients
received placebo. Patients on azithromycin showed a significant improvement in FEV1
and experienced less exacerbation in comparison with patients on placebo (57). In
another study, 27 CF patients were treated with oral clarithromycin (250 mg every other
day) for 12 months (58). A reduction in TNF-α and IL-8 levels in plasma and sputum
associated with a significant amelioration of lung functions was observed (58).
Stop signals and pro-resolution mediators of inflammation
The inflammatory response is a well ordered sequelae of events that physiologically
culminates with resolution and restitution at integrum. It is now clear that the resolution
phase of inflammation is an active process, tightly regulated by a wide number of
mediators. Thus, the understanding of mechanisms involved in resolution, may provide
the basis for alternative anti-inflammatory treatments.
Metabolism of unsaturated fatty acids generates a number of pro-resolution compounds.
In particular, arachidonic acid (AA) is converted by cooperation between lipoxygenases
into lipoxins (LX), whereas aspirin-treated cyclooxygenase 2 (COX-2) in cooperation
with 5-LO yields the 15-epi-LX (59). On the other side, eicosapentaenoic acid (EPA) is
converted by aspirin-acetylated COX-2 into resolvins of the E-series (RvE1), whereas
docosahexanoid acid (DHA) can give rise to protectins/neuroprotectins (PD1) or 17S
resolvins of the D-series (RvD1) when attacked by LO or 17R
-resolvins of the D-series
(AT-RvD1) in the presence of aspirin-acetylated COX-2 (60). LX and epi-LX as well as
resolvins and protectins exert potent anti-inflammatory bioactions in vitro and in vivo
(59,60). Interestingly, BALF from CF patients display decreased lipoxin A4 (LX4) levels
(61). In addition, a LXA4 stable analog suppressed neutrophilic inflammation and
reduced disease severity in a mouse model of CF (61). On the other hand, a deficiency in DHA, which is the precursor of protectins and resolvins, has been observed in CF (62), providing a rationale for DHA trials in CF (63). Administration to 5 CF patients of 70 mg of DHA/kg body weight/d for six weeks, determined a significant increase in tissue DHA levels (64). Long-term administration of DHA to Cftr
-/- mice resulted in a significant improvement of inflammatory liver disease (65). These observations indicate that alterations in endogenous pro-resolution signals may be also involved in CF inflammation. It may be therefore hypothesized that administration of pro-resolution drugs may represent an alternative therapeutic option to combat inflammation in CF. Concluding remarks
It is now clear that controlling inflammation is a challenging, however crucial, task in CF therapy. A variety of approaches have been experimented with mixed results (Table 1). It is essential to decode the key and peculiar circuits of CF inflammation to establish a successful treatment, since conventional anti-inflammatory drugs have shown limited therapeutic efficacy. If, on one side, there is a need for more, prospective clinical trials, on the other side the indications provided by basic science should be translated into novel approaches. In this respect, the synthesis and the use of pro-resolutions drugs may be worth pursuing.
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TABLE 1 ANTI-INFLAMMATORY DRUGS IN CF
Results and Remarks
Improvement in lung function. Serious adverse effects in long-term treatment 
Insufficient evidence of benefit or risk. Small populations studied.
Some improvement in FEV1. Evidence is too preliminary.
Consistent slow progression of lung disease. Modest risk of GI bleeding.
No data available in CF. Cardiovascular risk in long-term administration.
Reduction in inflammatory markers in BALF. Reduction in decay of lung
functions and risk of exacerbations. Longer follow up trials are needed.
Trial stopped because of serious respiratory adverse effects.
Modest improvement in exercise tolerance, respiratory symptoms and
inflammatory parameters. No conclusive evidence of benefit.
Significant reduction in sputum elastase activity and neutrophil burden. No
changes in pulmonary functions. More consistent evidence needed. Phase II
Increased NO formation. No changes in FEV1.
Down-regulation of pro-inflammatory cytokine expression in airway cells and
in alveolar macrophages. Under clinical evaluation.
No changes in respiratory functions or inflammation markers.
Prolonged inflammation in response to Pseudomonas aeruginosa
knockout mice. IL-10 improved survival of IL-10 knockout mice.
Suppression of neutrophil elastase. Reduction in pro-inflammatory cytokines
and PMNs in the induced sputum. NO changes in lung function.
Protection of rats from acute lung injury. Reduction of PMN influx in rat
airway after tracheal instillation of pooled sputum from children with CF.
Phase II clinical trial is underway in Europe.
Significant improvement in FEV1. Less exacerbations.
Reduction in TNF-α and IL-8 levels in plasma and sputum. Significant
Suppression of neutrophilic inflammation and reduction disease severity in a
Potent anti-inflammatory activity in vitro and in animal models. No data
Potent anti-inflammatory activity in vitro and in animal models. No data
Increase in tissue DHA levels in CF patients. Significant improvement of
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