Address correspondence to:
Departments of Biochemistry and Medicine
Tikrit University College of Medicine, Tikrit, IRAQ
Email: aminahamed2006@yahoo.com
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The prevalence of asthma in the United States has risen by 75% in the last 3 decades, with a particularly marked increase in children < 5 years of age (160%). [1] The reason for the surge in prevalence is unclear. A number of hypotheses have been proposed, including increased environmental exposures to "synthetic" materials and indoor allergens, decreased exposure to bacteria and childhood illnesses (the "hygiene" hypothesis), the increasing prevalence of obesity, changes in diet and antioxidant intake, increased exposure to cockroaches, changing meteorological patterns, and decreased use of aspirin [2-8]. In addition, cytokine imbalance or dysregulation occurring as a result of environmental exposures during infancy and early childhood is hypothesized to induce lifelong T-helper type 2 (allergic) dominance over T-helper type 1 (nonallergic) responses. T-helper type 2 dominance increases the risk for atopic diseases, including asthma. While most studies have focused on the effects of these factors after birth, some have suggested sensitization in utero [6,7,9].

A link between acetaminophen and bronchoconstriction was originally suggested in a case report of an aspirin-intolerant patient as early as 1967 by Chafee and Settipane [10]. Recently, with the rise in asthma prevalence, there has been renewed interest in the role of acetaminophen [11]. Concurrent with the use of acetaminophen, a large increase in asthma, particularly in the pediatric population, has been reported [11].

Various epidemiologic and quasi experimental studies have suggested a link between both therapeutic and overdose ingestion of acetaminophen and bronchoconstriction in certain individuals. Across European countries, asthma rates ecologically associated with acetaminophen use [12], have also been seen at the individual level. In a large population-based, case-control study [13] of young adults, daily and weekly use of acetaminophen was strongly associated with asthma. The relationship was much stronger for severe asthma. Aspirin avoidance did not appear to account for the positive results, as the association was found in those taking only acetaminophen as well as in those taking both analgesics.

A report found that increased frequency of acetaminophen use in 1990 to 1992 was associated with a subsequent risk of physician diagnosis of new-onset asthma diagnosed between 1990 and 1996 [14]. The risk of wheezing was increased twofold in 30-to 42-month-old children whose mothers frequently used acetaminophen prenatally during weeks 20 to 39 of gestation [15].

N-acetylcystine (NAC), a precursor of reduced glutathione (GSH), has been in clinical use for more than 30 years, primarily as mucolytic. In addition to its mucolytic action, NAC is being studied and utilized in conditions characterized by decreased GSH or oxidative stress [16]. Because of its hepato-protective activity, intravenous and oral administration of NAC have been used extensively in the management of acetaminophen poisoning [17].

NAC exhibits direct and indirect antioxidant properties. Its free thiol group is capable of interacting with the electrophilic groups of ROS [18].

NAC reduced H2O2-induced damage to epithelial cells in vitro [271] and NF-kB activation in some cells [19]. In addition to its effects on PMNs, NAC also influences the morphology and markers of oxidative stress in red blood cells (RBCs) [20]. Treatment with NAC may alter lung oxidant/antioxidant imbalance and reduced O2·- production by alveolar macrophages and decreased BALF PMN chemiluminescence in vitro [21]. Treatment with NAC resulted in a considerable reduction in elastase activity, in both the bronchoalveolar cavity and plasma, related to its property of scavenging HOCl [18].

Bleas et al [22] reported that Oral NAC exerts an antioxidant protective effect and attenuates pulmonary inflammation induced by antigen exposure in experimental asthma. In addition, oxidative stress stimulates mucin synthesis in airways, a process that is inhibited by NAC [23]. It has been reported that oral NAC reduces BHR to 5- hydroxytriptamine and the augmented eosinophil numbers elicited by allergen exposure in actively sensitized rats [22].

Enhancement of antioxidant defense mechanisms, therefore, seems a rational therapeutic option. Antioxidant therapy, including NAC, has been reported to be useful in the treatment of acute lung injury [24]. Understanding of the key elements of the redox control mechanism of IL-1B induced eotaxin and MCP-1 expression and production by HASMC, may indicate a new strategy in controlling airway inflammation [20,25]. Bleas et al [22] study provides some in vitro evidence that NAC, an antioxidant agent that has been used for many years as mucolytic drug, could also be useful in the treatment of more chronic inflammatory diseases such as asthma. It is not known, at the present time, whether NAC is capable of producing a beneficial effect in controlling the airways inflammation in-vivo. However, if NAC, a relatively harmless molecule, is able to exert an anti-inflammatory effect, this can be used in combination with existing, potent, but potentially more harmful , drugs. This hypothesis, however, needs further investigation [26]. Oxidative stress may increase the risk of asthma, contribute to asthma progression and decrease lung function. Previous research suggests that use of acetaminophen, which hypothesized to reduce antioxidant capacity in the lung, is associated with an increased risk of asthma. The above research outcome measures were epidemiological and clinical parameters. The purpose of this study was to evaluate the effect of acetaminophen on serum total antioxidant capacity and lipid peroxidation and the protective effect of N -acetylcystine in asthma. The study was approved by the ethics committee of our college, and written consent was obtained from all participating subjects.

Study Population:
The impact of therapeutic doses of paracetamol (BP 500 mg tablet, SDI, Samara) on serum total antioxidant capacity and malodialdehyde levels, were studied in asthmatic patients. A total of 43 asthmatic patients were enrolled in the study; 24 of them were afebrile and not receiving acetaminophen, and 19 were febrile and received acetaminophen 3 gm/ day from 0 - 7 days and 3 gm / day on 10th and 14th days. Venous blood samples collected from all patients in the two groups on day 15th of their enrollment in the study. Serum TAC and MDA were determined and compared between the two groups and to healthy control findings. N acetylcystine ( BP 600 mg tablet.

Azupharma, GmbH, Germany), a drug with antioxidant properties, was investigated for its beneficial therapeutic effects in preventing oxidative stress induced by acetaminophen in asthma. Thus the drug was given in a dose of 600 mg twice daily for 4 weeks to the above two groups and at the end of treatment course serum collected for determination of TAC and MDA.

The subjects included in the study were outpatients from the Asthma and Allergy Centre or Samara General Hospital outpatients Clinic. The diagnosis of asthma was performed by specialist physician and was established according to the National Heart Blood and Lung Institute / World Health Organization (NHLBI/WHO) workshop on the Global Strategy for Asthma [27]. Patients were excluded if they were smokers, if they had respiratory infection within the month preceding the study, a rheumatological illness, malignancy, diabetic, heart failure, history of venous embolisms, coronary heart disease and liver or kidney disease.

At enrollment, they all underwent full clinical examination, pulmonary function test, and blood sampling. Normal volunteers were also enrolled in the study as a healthy control. None of them had any previous history of lung or allergic disease and were not using any medication. They had a normal lung function test (FEV1 > 80%) and negative skin allergy test. General stool examination was performed for all patients and control to exclude parasitic infections. The sampling was performed during the period from May 2004 to December 2005. All samples were collected at morning following overnight fasting.

The study was approved by the ethics committee of our college and written consent was obtained from all participating subjects.

Determination of Total Antioxidant Capacity (TAC):
The method for serum TAC determination was as previously described by Kampa M et al [28]. In brief, in each tube 400 µl of crocin and 200 µl of serum sample were pipetted. The reaction was initiated with the addition of 400 µl of prewarmed (370C) ABAP (5 mg/ml), and crocin bleaching was made by incubating the plate in an oven for 60 - 75 minutes. Blanks consist of crocin, serum samples and phosphate buffer (400, 200, 400 µl respectively) were run in parallel. The absorbance was measured at 450 nm. A standard curve of the water soluble synthetic antioxidant Trolox, prepared prior to use, ranging from 0 - 10 µg/ml was equally assayed under the same conditions.
Determination of Malodialdehyde:

As the index of lipid peroxidation, serum MDA concentration was determined by measuring the thiobarbituric acid reactive substances (TBARS) according to the spectrophotometric method of Janero [29]. The TBARS was determined using OXITEK TBARS Assay kit from Zeptometrix Company.

A 100 ul of sodium doedecyl sulfate was added to the tubes that contain either serum sample or standard and mixed thoroughly. Then 2.5 ml of thiobarbituric acid/ buffer reagent was added down the side of each tube. The tube was covered and incubated at 95 o C for 60 minutes. The tube was then removed and cooled to room temperature in an ice bath for 10 minutes. After cooling the samples centrifuged at 3000 rpm for 15 minutes. The supernatant was removed from samples for analysis. The absorbance of supernatant was measured at 532 nm. Determination of MDA equivalent in µmol/ l in samples was by interpretation from standard curve.

Lung Function Test:
Computerised spirometer (Autosphiror, Discom-14, Chest Corporation, Japan) was used for measurement of FEV1 of the patients at their enrollment in the study and when indicated according to study design.

Statistical Analysis:
The values are reported as mean +/- SD and 95% confidence interval. For statistical analysis between groups paired t test was used. Pearson test was used for correlation analysis. The levels of each marker were compared between the study groups and control group, using SPSS computer package. P values of < 0.05 were considered significant.

TAC serum mean was significantly lower in asthmatic patients receiving acetaminophen (623 ± 216 µmol/l) than that in asthmatics not receiving the drug (876 ± 253 µmol/l; P< 0.005) and control group (1074 ± 207 µmol/l; P<0.0001)( Table 1). MDA mean serum level was significantly higher in the asthma group receiving acetaminophen (7.23 ± 2.82 µmol/l) than that in asthmatic patients not receiving the drug (4.39 ±1.84 µmol/l; P<0.005) and control group (2.24 ± 0.26 µmol/l; P<0.0001). Acetaminophen usage led to a significant reduction in FEV1 in asthmatic patients (82 ± 6) more than in control group (101±5; P<0.005) and asthmatic patients not receiving acetaminophen (96 ± 4; P<0.0001). (Table 1)

Thus acetaminophen usage leads to reduction in serum TAC and increase in lipid peroxidation and consequently this oxidative stress contributes to asthma progression and decrease in lung function. The oxidation index was 11.61 in asthmatic patients receiving acetaminophen and this was double that in asthmatic patients not receiving the drug (5) and about 6 times that of control group.

The chronic ingestion of therapeutic doses of acetaminophen depletes serum antioxidant capacity in asthmatic patients as this study indicated. NAC has antioxidant properties and was used effectively for treatment of acetaminophen poisoning. Thus in this study we investigated a possible beneficial effect of NAC when combined with acetaminophen in asthmatic patients. The drug was given in a dose of 600 mg twice daily for the previous two asthmatic groups for 4 weeks and after that TAC and MDA were measured (Table 2). The results indicated that NAC led to a significant increase in TAC (P<0.05) following the treatment course in asthmatic patients not receiving acetaminophen (986 ±118 µmol/l). However, the increase in TAC serum levels was with higher significance (P<0.025) in asthmatic patients group receiving combined acetaminophen and NAC (804 ± 294 µmol/l).

MDA serum levels decreased significantly (P<0.0005) in asthmatic groups receiving acetaminophen and NAC (4.62 ± 1.14 µmol/l). However the use of NAC by asthmatic patients not receiving acetaminophen led to decrease of serum MDA, but with lower significance (P<0.05). Another interesting finding in this study was that NAC led to significant increase in FEV1 (P<0.0001) in asthmatic patients receiving cetaminophen combined with NAC. Oxidative index reduced to half (5.75) following treatment with NAC in the acetaminophen receiving group. However, NAC improved significantly FEV1 (P<0.001) in asthmatic patients not receiving acetaminophen. Thus NAC administration to asthmatic patients effectively restores serum TAC and MDA to nearly normal levels. Therefore we suggest the use of combined therapy of acetaminophen and NAC to reduce the impact of acetaminophen on antioxidant defense in asthmatic patients.

Asthma prevalence has increased dramatically since the 1970s and currently affects 5-8% 0f the population [1]. Concurrent increases in asthma related to hospitalization and mortality suggest that the change in asthma prevalence did not result from greater diagnosis and detection alone [27], although, asthma related hospitalization and mortality appear to have declined since 1995 with the more widespread use of inhaled corticosteroids [30].

Various hypotheses have been proposed to explain the rise in asthma prevalence, including those relating to changes in early life antigen exposure [31] and to the obesity epidemic [32,33]. The rise in the prevalence and severity of asthma, however, also coincided with a large increase in the use of acetaminophen in the 1970s and 1980s [9].

This substitution of acetaminophen for aspirin was not evaluated inrandomized trials [14]. By contrast, ibuprofen was recently compared with acetaminophen for pediatric febrile illness in a large randomized, double blind clinical trial [34]. Among the subgroup of 1879 children with asthma, asthma related outpatient visits were significantly lower in the ibuprofen arm, and asthma hospitalization was non significantly reduced compared with the acetaminophen [34]. The trial did not include a placebo control, therefore it is uncertain whether ibuprofen decreased or acetaminophen increased asthma morbidity. Alternatively, the finding may have been due to chance [35].

A recently reported study [15] is another development in the story of how acetaminophen consumption may be a potential risk factor for developing asthma and atopy. The authors demonstrated a positive association between acetaminophen use in late pregnancy and subsequent asthma, wheezing and elevated serum IgE antibodies in 6 year old children. The data are consistent and build upon earlier observation of the same cohort demonstrating that frequent use of acetaminophen in late pregnancy is associated with increased risk of wheeze in the offspring aged 3 years old [13].

Sheehan et al [15] adds to the existing literature on acetaminophen and asthma that has developed since the report of the same research group in 2000 [13]. Another study reported from the USA, which indicated that taking acetaminophen for more than 14 days per month, had a 60% greater risk of incident asthma than those who never used acetaminophen [35]. Recently, data from New Zealand again demonstrated that current use of acetaminophen was associated with two fold increase in the prevalence of wheeze in children aged 6-7 years, with a smaller increase in wheeze in children who received acetaminophen in the first year of their life [36].

Association between acetaminophen consumption and asthma in adults may result from aspirin avoidance, or from the use of acetaminophen for asthma symptoms or for symptoms arising from the use of asthma medications [36]. The advantages of Sheehan studies in which the association is between maternal consumption and infant or child symptoms is that these alternative explanations are likely to operate [36]. Maternal asthma or allergy may still confound the association, as it may be associated with both asthma in the child and preferential acetaminophen use [36]. However, in the most recent study, the relationship persists after adjustment for maternal asthma [15].

All the above mentioned studies that suggest a link between acetaminophen use and development of asthma are epidemiologic studies. To our knowledge, only one study reported [37] that determines the effect of regular intake of acetaminophen on serum antioxidant capacity in healthy volunteers. It reports that chronic ingestion of maximum therapeutic doses of acetaminophen depletes serum TAC in healthy volunteers in as few as 14 days. It shows a trend toward reduced TAC over time. Another study investigated the effect of acetaminophen use on glutathione and antioxidant status in febrile children receiving repeated supra therapeutic doses [38]. TAC of serum and erythrocyte glutathione concentration were reduced in the group receiving supra therapeutic acetaminophen doses.

In the present study the association between acetaminophen use in asthmatic patients and changes in their serum TAC and MDA as parameters of oxidative stress was evaluated. Serum TAC significantly lowers in asthmatic patients receiving acetaminophen than in asthmatics not receiving the drug and control subjects. In addition, MDA serum levels were significantly higher in the asthma group receiving the acetaminophen than in asthmatics not receiving the drug and the control group. FEV1 of asthmatic patients reduced significantly after treatment with acetaminophen and it was significantly lower than that for asthmatic patients group not receiving the drug and that of the control group.

The acetaminophen use in asthmatics as this study indicated, leads to a reduction in serum TAC and increase in lipid peroxidation and consequently these oxidative stresses contribute to asthma progression and decrease in lung function. The oxidation index was two fold higher in the asthmatic group receiving the drug than in the asthmatic not receiving acetaminophen and about six times than that of the control group. Acetaminophen related brochospasm has been reported for at least 39 years in a subset of patients with asthma [10]. Acetaminophen provokes bronchospasm in up to 35% of patients with stable, aspirin sensitive asthma [11,39,40]. Reactions generally are milder than seen after aspirin challenge and occur with a high, but clinically relevant, dose of acetaminophen. Acetaminophen related bronchospasm also has been demonstrated in some patients of no history of aspirin sensitive asthma. The mechanism for this phenomenon is unclear, but may involve glutathione [11]. Acetaminophen decreases the level of glutathione in the liver, kidneys and lungs [41,42]. These decreases are dose dependent. Overdose levels of acetaminophen are cytotoxic to pneumocyte and cause acute lung injury, whereas nontoxic, therapeutic doses produce smaller, but significant, reductions in glutathione levels in type II pneumocytes and alveolar macrophages [43].

Oxidative stress in asthma occurs from the production of ROS in the lung by inflammatory cells. ROS causes contraction of airway smooth muscle and release of leukotrines and other secondary inflammatory mediators, leading to BHR and bronchoconstriction [44]. The importance of glutathione pathway in asthma is reinforced by the finding that polymorphisms in glutathione - s- transferase are associated with increased susceptibility to pediatric asthma and with slowed lung function growth in childhood [45].

If the association between acetaminophen consumption and asthma is causal, then as well as identifying a new risk factor for asthma, the proposed mechanism of this biological effect provides further support for the hypothesis that an imbalance of oxidant / antioxidant equilibrium influences susceptibility to developing asthma, with glutathione metabolism [46] in particular appearing to have a pivotal role. It is hypothesized that the mechanism by which acetaminophen would increase the risk of asthma is through depletion of reduced glutathione leading to a decrease in pulmonary antioxidant defenses [14,15].

Evidence that administration of therapeutic doses of acetaminophen can influence oxidative status is available with the finding of this study and the recent reports of a decrease in TAC [37], and if this effect is replicated in the lungs then it is likely that they would be more susceptible to oxidative insults [47].

As the purpose of the lungs is to permit transfer of gases including oxygen, they are exposed to higher concentrations of oxygen than other tissues, and hence are more at risk of oxidant induced injury and thus require antioxidant defenses to prevent permanent tissue damage [47]. The data from the present study and Shaheen et al [15] contribute to the hypothesis that oxidant / antioxidant equilibrium is important with regard to asthma, a concept that has developed over the past 20 years. The extent to which a high oxidant load is causally associated with asthma rather than being a secondary consequence of the inflammatory processes that accompany asthma remain unclear [47]. However, the data from the aforementioned perspective studies that exposure to a drug with pro - oxidant qualities such as acetaminophen increases the risk of subsequent asthma, are supportive of the more general hypothesis that a greater oxidative burden has a causal role in the pathogenesis of asthma [47].
Host antioxidant defenses may also be modified by the environment and are also considered potentially important with regards to asthma [48]. Those with lower endogenous antioxidant capacity as assessed by dietary intake [49], or serum markers of dietary antioxidants [2] are more likely to have incident or prevalent asthma, although studies have been inconsistent. The more pertinent measurement of lung antioxidant status has proven to be difficult to measure, but the non invasive measurement such as the use of exhaled markers of pulmonary disease [50] have also demonstrated increased oxidative activity in those with asthma compared with those without. . More invasive techniques such as BAL have demonstrated reduced levels of antioxidants such as vitamin C, vitamin E and urate, with higher concentrations of glutathione in those with asthma compared with those without the disease [51,52]. One interpretation of these observations is that the increased oxidative burden associated with asthma results in a reactive increase in the lung antioxidant capacity in the form of increased pulmonary glutathione [50], while subsequently depleting systemic antioxidant reserves as reflected in lower levels in the blood.

In vitro studies demonstrating that oxidative stress results in increased expression of the pro inflammatory transcription factors, nuclear factor KB and activator protein-1, provide one possible mechanism of how oxidative stress may promote an inflammatory condition such as asthma at cellular level [47].

As the concept that oxidant / antioxidant balance may influence the development of asthma becomes more established, the potential for prevention and therapeutic intervention needs to be established. These would aim to reduce the risk of developing asthma or modify the severity of the disease. As reported there was a link between frequent use of acetaminophen and asthma incidence and severity [15]. In addition, administration of the drug to normal individuals, led to reduction in TAC [37]. In febrile non-asthmatic children acetaminophen administration reduced TAC, GSH, SOD and increased aspartate aminotransferase activity significantly [38]. Although, the chronic ingestion of therapeutic dose of acetaminophen in asthmatic patients depletes serum TAC, as this study indicated.

N acetylcystine is an antioxidant drug commonly used in clinical practice [53], especially for the treatment of acetaminophen poisoning. On the basis of the above mentioned facts the time has come to evaluate the use of combination of NAC with acetaminophen in asthmatic patients. Thus their combination leads to a significant increased in serum TAC, accompanied with significant reduction in MDA serum levels. Also, the combination of both drugs cause significant improvement of FEV1 and reduction of oxidation index. Two possible antioxidant mechanisms have been proposed for this thiol containing antioxidant [53]. Firstly, NAC may have direct free radical scavenging properties. ROS may react with NAC resulting in the formation of NAC disulphide [18,40]. Secondly, and of more importance, NAC may also exert its antioxidant effects indirectly by facilitating GSH biosynthesis [21].
A reduction in the levels of various markers of inflammatory activity, such as ECP, lactoferrin and antitrypsin was found after administration of NAC [54]. Treatment with NAC resulted in a considerable reduction in elastase activity, in both the BAL fluid and plasma, related to its property of scavenging HOCl [18].

Oral administration of NAC before antigen exposure of a sensitized rat, a widely used experimental model for asthma, resulted in attenuation of antigen induced augmented lipid peroxidation and altered glutathione status, suppression of the nuclear factor Alfa levels and enhanced inducible nitric oxide synthase, intracellular adhesion molecule - 1, and mucin MUC5AC expression that follows allergen exposure and a marked decrease in airway hyperresponsiveness, bronchoalveolar lavage fluid eosinophil number and exudation after antigen challenge [22]. Other animal studies [55,56] reported that NAC administration reduces serum and plasma MDA levels, plasma NO and increases plasma SOD, CAT, GSH and GPX. In addition, NAC administration was with modulatory effect on genes [19,57].

Reactive oxygen species are involved in the activation of several mitogen activated protein kinases (MAPK), key players in the production of several cytokines [54]. NAC decreased the expression of eotoxin and monocyte chemotactic protein -1 in human airway smooth muscle cells. Also NAC decreased the IL-1B induced production of ROS, as suggested by a reduction in the 8- isoprostan production [54]. The potential therapeutic value of antioxidants including NAC awaits support from controlled clinical trials that evaluate oral versus inhaler route of administration.

N acetycystine is a thiol compound with antioxidant properties [89] that reduces the lung damage produced by oxidant stress in different experimental models and exerts beneficial effects in pulmonary diseases in which oxidant stress appears pathogeneticaly relevant [26]. In experimental models of allergic asthma, antioxidant, and anti inflammatory and anti hyperresponsiveness effect of oral NAC was observed [22,58]. Allergen challenge of the peripheral airways in atopic asthmatics has been demonstrated to produce immediately, significant amounts of ROS released locally from eosinophils and other inflammatory cells [59]. Blesa et al [22] reported that antigen challenge causes increase in lipid peroxidation levels and decreased GSH/GSSH ratio, confirming the existence of oxidative stress. An increase in GSSH and decrease in GSH level in epithelial lining fluid early after antigen challenge has been reported recently in asthmatics [60]. Oral treatment with NAC is efficient at attenuating the augmented lipid peroxidation and GSSH levels, and reversing the decreased GSH/GSSH ratio, confirming its antioxidant properties in this animal model [22].

Since the presence of oxidative stress was demonstrated for rat models of allergic asthma, activation of a number of inflammatory elements reported to be oxidant sensitive, including transcription factors like NF-kB and cytokines such as TNF Alfa; and expression of gene like iNOS, intracellular adhesion molecule -1 (ICAM-1) and MUC5AC were sought [17,19,22,25,57,61]. Furthermore, treatment with an antioxidant should attenuate these activated factors as well as prove beneficial against the typical features of experimental asthma such as airway hyper-responsiveness, eoisinophilia and exudation.

NF- kB is considered as a pivotal transcription factor in chronic inflammatory diseases and very sensitive to oxidants as well as other stimuli [19]. Augmented activation of NF-kB has been demonstrated in the airways and inflammatory cells of asthmatic patients as well as in experimental asthma [19]. The antioxidant properties of NAC may contribute directly to its inhibitory effects on NF-kB activation [22]. Alternatively, NF-kB activation may result from the release of TNF Alfa, which induces generation of ROS [50].

TNF Alfa is a proinflammatory cytokines that has been implicated in the pathogenesis of asthma and considered a potential target for therapeutic intervention. This increased TNF Alfa level was attenuated in NAC treated animals, a finding consistent with the suggestion that GSH status regulates TNF Alfa production in vivo and with the inhibition by NAC of the increase in TNF Alfa observed in various studies [17,19].
The ICAM-1 gene contains NF-kB binding sites and its expression is oxidant sensitive [57]. The expression or airway and endothelial ICAM-1 are enhanced by TNF Alfa and other inflammatory cytokines [57]. Therefore, various elements may contribute to the enhanced expression reported by Blesa et al [22] and the inhibition found for NAC would be consistent with other reports [62,63].

Mucus overproduction is often observed in airway inflammation and contributes to airway obstruction in asthma. Recent work indicates that
oxidative stress stimulates mucin synthesis in airways particularly synthesis of MUC5AC [23]. Treatment with NAC blocked this early expression of MUC5AC. These results confirm that oxidative stress appears important in the excessive production of mucin airways, and antioxidants are effective at suppressing the enhanced expression of mucin genes in experimental asthma [58].

Consequential to these inhibitory effects of antioxidant treatment on treanscription factors, inflammatory cytokines and genes, there should be experimental evidence of beneficial effects of NAC on characteristic features of allergic asthma. NAC was effective at reducing both BHR and the elevated BALF eosinophil numbers [22]. Several lines of evidence suggest that the production of oxygen radicals is implicated in the airway response to allergen [46]. Thus the antigen induced hyper-responsiveness was found to correlate significantly with the increases in oxygen radicals release from BALF cells in sensitized animals [48].

The oxidant transcription factor NF-kB appears relevant to eosinophilia in allergic asthma [19]. Also, cell trafficking into inflammatory sites depends on the sequential expression of cell adhesion molecules, which are modulated by oxidant species; in particular, ICAM-1 is important for induction of BHR in vivo as well as eosinophil migration into inflamed lung [57]. Therefore, the reduced BHR and eosinophilia produced by NAC may also be related to its antioxidant properties.

In conclusion, oral administration of NAC attenuates the oxidative stress induced by acetaminophen in asthmatic patients. In keeping with these results the reported findings from several studies in animal models indicated that NAC 1) attenuate antigen induced lipid peroxidatin and altered glutathione status,;2) suppression of NF-kB activation, mucin MUC5AC expressions, ICAM-1,elevated tumor necrosis factor Alfa levels, 3) a marked decrease in BHR and BALF eosinophil number and exudation after allergen challenge. These results confirm that oxidative stress may contribute to the pathogenesis of asthma. The potential therapeutic value of antioxidant including NAC awaits support from controlled clinical trials.

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