**3. Strategies to block NF-κB activation**

Several strategies have been proposed to block the activation of NF-κB. An extensive diversity of molecules (both natural and synthetic) has been highlighted as having an effect on activation of NF-κB and being able suppress it. These compounds suppress NF-κB

Lung and Systemic Inflammation in COPD 13

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively applied to improve the therapeutic status of chronic inflammatory states. The most widely hypothesis for the inhibitory property of these compounds on the inflammatory response supposes that

NSAIDs such as Aspirin and sodium salicylate correlate with NF-κB inhibition. At concentrations measured in the serum of patients treated with these drugs for chronic inflammatory situations, both aspirin and salicylate suppress NF-κB activation, and aspirin has been demonstrated to inhibit the activation of the IκB kinase complex [97, 100]. In particular, Aspirin and sodium salicylate prevent NF-κB nuclear translocation by blocking IkBα phosphorylation and degradation (Figure 1) [3, 100]. These drugs also inhibit TNF-αinduced mRNA transcription of adhesion molecules such as ICAM-1 in endothelial cells. Penetration of neutrophils from endothelial cells can be prevented following NF-κB inhibition in these cells. Recently, Yin *et al.* have reported that Aspirin can bind to and prevent the kinase activity of IKKβ by decreasing its capacity to bind ATP. Other NSADs, such as tepoxaline, defereoxamine, and ibuprofen, are also capable of suppressing NF-κB

An aminosalicylate derivative with anti-inflammatory aspects, mesalamine, prevents IL-1– mediated activation of p65 phosphorylation without suppressing IκBα degradation [64]. Indomethacin, is another NSAID, is able to inhibit inflammatory responses via suppressing COX activity, but it does not prevent activation of the NF-κB pathway [64]. Sulindac is illustrated in Figure 1 as a NSAID that is structurally correlated with indomethacin and can

These findings suggest that inhibition of the NF-κB pathway might be implicated in the antiinflammatory pathways as well as participation of NSAIDs in growth inhibitory properties.

NF-κB is one of the most important transcription factors and has an important role in inflammatory special lung disease [6]. The exact pathophysiological mechanism of NF-κB that leads to inflammation continues to be better understood. Pharmacologic therapy used for blocking this molecule can be useful for treatment of lung disease. The major recommendation for further research is to define the exact molecular mechanisms of each inflammatory lung disease that involves NF-κB. This is critical because the glucocorticoids which benefit patients with asthma do not work for COPD. Future research will to elucidate

We thank members of our laboratory in Chemical Injury Research Center (CIRC)

[1] Haddad, J.J.; Science review: Redox and oxygen-sensitive transcription factors in the

regulation of oxidant-mediated lung injury: Role for nuclear factor-κB. Critical

inhibit activation of the NF-kB pathway by suppressing IKK activity [64, 97].

new methods of treatment for those patients [101].

Baqiyatallah Medical Sciences University.

Care, 2002, 6, 481-490.

NSAIDs inhibit COX activity to suppress prostaglandin synthesis [64].

activity [100].

**4. Conclusion** 

**5. Acknowledgement** 

**6. References**

activation through various pathways by blocking NF-κB activation. Subsequent information has provided strategies for suppressing NF-κB activation in response to different type of stimuli. Both steroids and nonsteroidal anti-inflammatory agents are helpful (Table 2). Hence, it is important to get a better understanding of the activation of NF-κB and release of prostaglandins [64]. Glucocorticoids, including dexamethasone and prednisone, are commonly prescribed for their anti-inflammatory and immunosuppressive effects [97-99]. These components interact with the steroid receptor and cause reduction of the expression of particular genes that control the inflammatory procedure. NF-κB can be inhibited via glucocorticoids in different ways. Dexamethasone induces the expression of IκBα, which causes retention of NF-κB in the cytoplasm, especially of p65. Synthesis of IκBα by dexamethasone is likely to be dependent on p65 in pre-existing NF-κB complexes. These findings show that quick degradation of IκBα may be blocked by consequent expression of IκBα following dexamethasone treatment. Another pathway implicated in glucocorticoidmediated repression of the NF-κB is that dexamethasone may inhibit the expression and p65-dependent transactivation in endothelial fibroblasts in murine models, but it does not have any effect on the IκB level. In the same way, dexamethasone alters NF-κB–mediated transcriptional activity in endothelial cells, but it does not alter IκB levels either [64].


Table 2. Therapeutic agents and drugs which block NF-κB activation.

activation through various pathways by blocking NF-κB activation. Subsequent information has provided strategies for suppressing NF-κB activation in response to different type of stimuli. Both steroids and nonsteroidal anti-inflammatory agents are helpful (Table 2). Hence, it is important to get a better understanding of the activation of NF-κB and release of prostaglandins [64]. Glucocorticoids, including dexamethasone and prednisone, are commonly prescribed for their anti-inflammatory and immunosuppressive effects [97-99]. These components interact with the steroid receptor and cause reduction of the expression of particular genes that control the inflammatory procedure. NF-κB can be inhibited via glucocorticoids in different ways. Dexamethasone induces the expression of IκBα, which causes retention of NF-κB in the cytoplasm, especially of p65. Synthesis of IκBα by dexamethasone is likely to be dependent on p65 in pre-existing NF-κB complexes. These findings show that quick degradation of IκBα may be blocked by consequent expression of IκBα following dexamethasone treatment. Another pathway implicated in glucocorticoidmediated repression of the NF-κB is that dexamethasone may inhibit the expression and p65-dependent transactivation in endothelial fibroblasts in murine models, but it does not have any effect on the IκB level. In the same way, dexamethasone alters NF-κB–mediated

transcriptional activity in endothelial cells, but it does not alter IκB levels either [64].

Table 2. Therapeutic agents and drugs which block NF-κB activation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively applied to improve the therapeutic status of chronic inflammatory states. The most widely hypothesis for the inhibitory property of these compounds on the inflammatory response supposes that NSAIDs inhibit COX activity to suppress prostaglandin synthesis [64].

NSAIDs such as Aspirin and sodium salicylate correlate with NF-κB inhibition. At concentrations measured in the serum of patients treated with these drugs for chronic inflammatory situations, both aspirin and salicylate suppress NF-κB activation, and aspirin has been demonstrated to inhibit the activation of the IκB kinase complex [97, 100]. In particular, Aspirin and sodium salicylate prevent NF-κB nuclear translocation by blocking IkBα phosphorylation and degradation (Figure 1) [3, 100]. These drugs also inhibit TNF-αinduced mRNA transcription of adhesion molecules such as ICAM-1 in endothelial cells. Penetration of neutrophils from endothelial cells can be prevented following NF-κB inhibition in these cells. Recently, Yin *et al.* have reported that Aspirin can bind to and prevent the kinase activity of IKKβ by decreasing its capacity to bind ATP. Other NSADs, such as tepoxaline, defereoxamine, and ibuprofen, are also capable of suppressing NF-κB activity [100].

An aminosalicylate derivative with anti-inflammatory aspects, mesalamine, prevents IL-1– mediated activation of p65 phosphorylation without suppressing IκBα degradation [64]. Indomethacin, is another NSAID, is able to inhibit inflammatory responses via suppressing COX activity, but it does not prevent activation of the NF-κB pathway [64]. Sulindac is illustrated in Figure 1 as a NSAID that is structurally correlated with indomethacin and can inhibit activation of the NF-kB pathway by suppressing IKK activity [64, 97].

These findings suggest that inhibition of the NF-κB pathway might be implicated in the antiinflammatory pathways as well as participation of NSAIDs in growth inhibitory properties.
