**6. Therapeutic alterations of lung inflammation-induced systemic responses**

Several observational studies suggest that statins may represent a useful therapeutic adjunc‐ tive modality for ALI/ARDS: a benefit of prior statin use was found in patients with pneumonia [150-152]. Similarly, other studies showed a reduction in the frequency of COPD exacerbations, hospitalization, and mortality after statin therapy, which may be a result of a direct effect on lung inflammation, an impact on the systemic consequences of COPD, or both [153-161]. These studies indicate that statins are effective in decreasing lung and systemic inflammation in

Nature and Consequences of the Systemic Inflammatory Response Induced by Lung Inflammation

http://dx.doi.org/10.5772/57392

97

A systemic response is a hallmark of both acute and chronic lung inflammatory conditions. The nature and magnitude of this systemic response differs depending on the nature and magnitude of the inflammatory response in the lung. Mediators generated in the lung as part of the lung inflammatory response, translocate to the systemic circulation, contributing to the systemic response. This systemic response has significant downstream adverse consequences on distant organs suggesting it is as an important therapeutic target. Therapeutic tools to modify and alter the systemic response induced by lung conditions, are still lacking and need

Department of Medicine, UBC James Hogg Research Centre, St. Paul's Hospital, University

[1] Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000

The authors acknowledge Dr. Katherine Thain for writing assistance.

\*Address all correspondence to: stephan.vaneeden@hli.ubc.ca

humans *in vivo*.

**7. Conclusion**

further study.

**Acknowledgements**

**Author details**

**References**

Kunihiko Hiraiwa and Stephan F. van Eeden\*

of British Columbia, Vancouver, Canada

May 4;342(18):1334-49.

Themediators of systemic responses to lung inflammationare clinicallyusefultools with which to grade the severity of lung inflammation or to use as biomarkers for following the progres‐ sion of the disease. Neutralization of these mediators using effector molecules termed "immu‐ noresolvents" may prove useful in attenuating the downstream consequences of the systemic inflammatory response. Potential advantages of immunoresolvents lie in the possibilities of bothattenuatingleukocyte activationanddecreasingrecruitmentintotissues,therebyreducing organ damage. However, in a study with more than 10,000 patients with sepsis, anti-inflamma‐ tory agents designed to inhibit specific host mediators, for example anti-TNF antibodies and IL-1 receptor antagonists, failed to show benefit, despite promising preclinical testing [133]. Similarly, another multicenter, randomized, double-blind study in patients with moderate to severe COPD showed that infliximab (anti-TNF-α monoclonal antibody) had no therapeutic benefit in reducing acute exacerbation of COPD [134]. Although many proinflammatory neutralizing therapies have the potential to be useful, they also evoke some unwanted effects, for example, TNF-specific antibody therapy reduces TNF-α concentrations but is also associat‐ ed with increasedsusceptibility to infections and malignancies [134]. Clearly, immunosuppres‐ sion is a critical drawback to some treatments and new therapeutics targeting resolution of inflammation would be required to circumvent this side effect.

The anti-inflammatory cytokine IL-10 balances the proinflammatory response and serves to limit and terminate the cascade of proinflammatory cytokines. Research shows that treatment with IL-10 reduces neutrophil and leukocyte recruitment and decreases proinflammatory cytokine-production in lung inflammation [135-138], underlining the importance of balancing the acute inflammatory response and suggesting that treatment using a combination of different therapeutic agents to alter outcome in the systemic inflammatory milieu may be more successful.

Recently several classes of pro-resolving mediators have been identified, including resolvins, protectins and maresins [139]. These specialized lipid mediators are derived via enzymatic processing from dietary omega-3 polyunsaturated fatty acids and have anti-inflammatory activity in lung inflammation [140, 141].

Originally designed to lower cholesterol, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase class of drugs, also called "statins", are recognized as anti-inflammatory agents [142]. Experimental observations suggest that these agents have pleiotropic anti-inflammatory properties *in vitro* including the inhibition of isoprenoid synthesis, which leads to the inhibition of small proinflammatory signaling GTPases such as Rho, Rac and Cdc42 [143, 144]. Animal studies have demonstrated that statins attenuate lung injury in ischemia-reperfusion, perito‐ nitis and aerosolized LPS models [145-147]. In addition, statins downregulate the PM10 induced overactive bone marrow by attenuating systemic inflammatory responses such as the recruitment and activation of alveolar macrophages and polymorphonuclear leukocytes, as well as reducing local proinflammatory cytokine production and promoting the clearance of PM10 particles from lung tissues to regional lymph nodes [148, 149].

Several observational studies suggest that statins may represent a useful therapeutic adjunc‐ tive modality for ALI/ARDS: a benefit of prior statin use was found in patients with pneumonia [150-152]. Similarly, other studies showed a reduction in the frequency of COPD exacerbations, hospitalization, and mortality after statin therapy, which may be a result of a direct effect on lung inflammation, an impact on the systemic consequences of COPD, or both [153-161]. These studies indicate that statins are effective in decreasing lung and systemic inflammation in humans *in vivo*.

#### **7. Conclusion**

**6. Therapeutic alterations of lung inflammation-induced systemic**

inflammation would be required to circumvent this side effect.

PM10 particles from lung tissues to regional lymph nodes [148, 149].

Themediators of systemic responses to lung inflammationare clinicallyusefultools with which to grade the severity of lung inflammation or to use as biomarkers for following the progres‐ sion of the disease. Neutralization of these mediators using effector molecules termed "immu‐ noresolvents" may prove useful in attenuating the downstream consequences of the systemic inflammatory response. Potential advantages of immunoresolvents lie in the possibilities of bothattenuatingleukocyte activationanddecreasingrecruitmentintotissues,therebyreducing organ damage. However, in a study with more than 10,000 patients with sepsis, anti-inflamma‐ tory agents designed to inhibit specific host mediators, for example anti-TNF antibodies and IL-1 receptor antagonists, failed to show benefit, despite promising preclinical testing [133]. Similarly, another multicenter, randomized, double-blind study in patients with moderate to severe COPD showed that infliximab (anti-TNF-α monoclonal antibody) had no therapeutic benefit in reducing acute exacerbation of COPD [134]. Although many proinflammatory neutralizing therapies have the potential to be useful, they also evoke some unwanted effects, for example, TNF-specific antibody therapy reduces TNF-α concentrations but is also associat‐ ed with increasedsusceptibility to infections and malignancies [134]. Clearly, immunosuppres‐ sion is a critical drawback to some treatments and new therapeutics targeting resolution of

The anti-inflammatory cytokine IL-10 balances the proinflammatory response and serves to limit and terminate the cascade of proinflammatory cytokines. Research shows that treatment with IL-10 reduces neutrophil and leukocyte recruitment and decreases proinflammatory cytokine-production in lung inflammation [135-138], underlining the importance of balancing the acute inflammatory response and suggesting that treatment using a combination of different therapeutic agents to alter outcome in the systemic inflammatory milieu may be more

Recently several classes of pro-resolving mediators have been identified, including resolvins, protectins and maresins [139]. These specialized lipid mediators are derived via enzymatic processing from dietary omega-3 polyunsaturated fatty acids and have anti-inflammatory

Originally designed to lower cholesterol, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase class of drugs, also called "statins", are recognized as anti-inflammatory agents [142]. Experimental observations suggest that these agents have pleiotropic anti-inflammatory properties *in vitro* including the inhibition of isoprenoid synthesis, which leads to the inhibition of small proinflammatory signaling GTPases such as Rho, Rac and Cdc42 [143, 144]. Animal studies have demonstrated that statins attenuate lung injury in ischemia-reperfusion, perito‐ nitis and aerosolized LPS models [145-147]. In addition, statins downregulate the PM10 induced overactive bone marrow by attenuating systemic inflammatory responses such as the recruitment and activation of alveolar macrophages and polymorphonuclear leukocytes, as well as reducing local proinflammatory cytokine production and promoting the clearance of

**responses**

96 Lung Inflammation

successful.

activity in lung inflammation [140, 141].

A systemic response is a hallmark of both acute and chronic lung inflammatory conditions. The nature and magnitude of this systemic response differs depending on the nature and magnitude of the inflammatory response in the lung. Mediators generated in the lung as part of the lung inflammatory response, translocate to the systemic circulation, contributing to the systemic response. This systemic response has significant downstream adverse consequences on distant organs suggesting it is as an important therapeutic target. Therapeutic tools to modify and alter the systemic response induced by lung conditions, are still lacking and need further study.
