**7.1 "Stressing" the oxidative stress, inflammation and autoimmunity**

Oxidative stress does exist in the lungs and it is inevitable, having in mind its physiology. Keeping its balance is a kind of self-protection. COPD is obviously a disease of disbalance oxi/antioxidant, protease/antiprotease, apoptosis/proliferation, acetylases/deacetylases. In most cases COPD develops in smokers that makes us think that it necessarily is related to smoking, but why only 20% of smokers develop COPD? Moreover how can we explain the presence of non-smoker 's COPD? Is this another disease? If not can we say that it is a proteinopathy? A proteinopathy that sets a disbalance in lung cells even in the absence of exogenous noxa; a reason for sending a "danger" signal to the innate immunity that acts on default and instead of helping additionally stresses the already "stressed cells". Could it be that COPD in smokers is also proteinopathy, but acquired? There are not enough studies that let us make certain conclusions about the role of chaperones, particularly of heat shock proteins in COPD. There is only data that let us make hypotheses.

Chronic Obstructive Pulmonary Disease - Chaperonopathology 93

cross-reactivity between bacterial HSP and human HSP. Assuming this we can hypotheisize that exacerbations in COPD may reflect antigenic mimicry – a cross-reactivity between the self-antigenic HSP-peptide complexes accumulated in lung cells and the evolutionary conserved HSP of the infectious viruses and bacteria. Determining the levels of HSP65

Exacerbations could also be a massive spillage of extracellular heat shock proteins that

Despite being or not a chaperonopathy, it will certainly be of interest to know whether the chaperones within the heterocomplex (HSP90/HSP70/GR) of the glucocorticosteroid receptor are related to corticosteroid resistance and if so how could this be modified? How is HSP90 involved in the telomere assembly and how can be manipulated to deter the telomere shortening and lung ageing? If Toll-like receptors and danger molecules as HSP 70 are the primary triggers of the immune response in COPD lung how effective will be their inhibiting? If COPD is a chaperonopathy how can we booster the chaperones instead of restoring the balance at so many levels - acetylase/deacetylase; oxidation/antioxidation; proteases/antiproteases? Is it reasonable to think that resuming one side of the problem as the application of sirtuin agonists, antioxidants, steroids would be a solution? Isn't it more reasonable to think of the natural protectors of these molecules that ''chaper'' (keep) them

There is scarce data on the role of chaperones in the molecular pathogenesis of COPD. The contemporary techniques – proteomics (MALDI-TOFF) and transcritpomics (SAGE – serial analysis of gene expression) show overexpression of both high molecular weight – HSP70 and small heat shock proteins – hem-oxygenase -1, HSP27 in lung cell lysates. Far more studies are dedicated to the high levels of circulating extracellular heat shock proteins, representing them as a trigger for Toll-like receptor mediated immune response – HSP70, or as a panel of diagnostic markers in COPD – HSP90, HSP70, HSP27. Presuming the biological functions of the chaperone system, its significance in protecting cells from "stress", its large collaboration with the immune system and importance of preserving the proper functioning and balance of the proteome within cells it is undoubtedly necessary to further elucidate

Abidoye O, Ferguson MK, Salgea R (2007). Lung carcinoma of African Americans *Nat Clin* 

Aggeli IK, Beis I, Gaitanaki C.(2008)Oxidative stress and calpain inhibition induce alpha B-

crystallin phosphorylation via p38-MAPK and calcium signalling pathways in

trigger the Toll-like receptors and thus induce immune response.

during exacerbations could give a clue.

**7.3 Treatment** 

from alteration?

**8. Conclusions** 

**9. References** 

their place in COPD etiology and progression.

H9c2 cells. *Cell Signal* 20:1292-1302.

*Pract Oncol*, 4; 118-129.

Can we assume that: In smokers' lungs, cells are exposed to additional stress, which acquires the intensive assistance of chaperones to maintain their proteins functionally available. In some individuals the chaperone system cannot adapt to the new set-point. The balance is disturbed. The cells are "stressed" and send signals for help. At the same time, however, there is already a depletion of chaperones and accumulation of abnormal proteins that appear as a result of the disbalance (proteinopathy/chaperonopathy) and this is another reason for sending "danger signals" to the immune system. These "danger signals" could themselves be heat shock proteins as the studies present. The "danger signals" bind to Toll-like receptors, which according to Doz et al, are essential for triggering the inflammation in COPD. Neutrophils are sequesterd in the pulmonary circulation and themselves become "stressed" Obviously something "happens" to their cytoskeleton as they become less deformable and retained. It is highly probable that their small heat shock proteins could not restore the cytoskeletal damage. Their F-actin probably cannot reorganize and form the lamelipodia and fillopodia needed for migration. Thus instead of protectors, neutrophils become generators of oxidative stress but also of inflammatory mediators - that is their cell-type specific response to stress. The immune system is activated. An inflammatory response follows. The innate immunity is triggered. Dendritic cells are already activated through their Toll-like receptors and the adoptive cell response becomes engaged. By that time the accumulation of modified proteins is still going on, the chaperone system and energy balance are overloaded. Instead of resuming the misfolded proteins, HSP – peptide, self-antigenic complexes accumulate in cells. Autoimmunity probably appears as an epiphenomenon. Rather than being resolved the problem persists, accelerated by the induction of an autoimmune inflammation. Despite performing their own cellular functions chaperones are trying to keep the other proteins. The cellular physiology is disturbed and a lot of cells commit a suicide. This leads to the spillage of "danger molecules", modified proteins, and self-antigenic products, that additionally activate the immune system. Inflammation persists despite of the elimination of the primary noxa and is even augmented by the immune cells. The "stressed lung cells" are sending danger signals to the immune system but instead of altruistic response they are put under even severe stress. The disbalance between proteins - acetylase/deacetylase; oxidation/antioxidation; proteases/antiproteases – changes the phenotypic characteristic of lung cells, as well as their environment – tissue remodelling follows. The functional characteristics of lung cells is already irreversibly deteriorated.

It is highly probabale that COPD smokers have chaperonopathy, affecting their cells as a whole but as lungs are the primary organ proteomic analysis of lung cells lysates will probably help most unraveling the puzzle. Microdissection techniques on epithelial cells should be used in patients with GOLD-0 and be compared to GOLD- I-II, GOLD – III-IV. It would be more reasonable to select patients considering phenotypes in COPD.

It would be interesting to find the role of extracellular HSP70 in COPD etiology an progression. The ''danger signal'' that stimulates inflammation through Toll-signalling.

#### **7.2 Exacerbations – A spillage of HSP, or antigenic mimicry?**

There is a lot of data about inflammatory and autoimmune (neurodegenerative, degenerative joint diseases, atherosclerosis, diabetes type I) diseases triggered as a result of cross-reactivity between bacterial HSP and human HSP. Assuming this we can hypotheisize that exacerbations in COPD may reflect antigenic mimicry – a cross-reactivity between the self-antigenic HSP-peptide complexes accumulated in lung cells and the evolutionary conserved HSP of the infectious viruses and bacteria. Determining the levels of HSP65 during exacerbations could give a clue.

Exacerbations could also be a massive spillage of extracellular heat shock proteins that trigger the Toll-like receptors and thus induce immune response.
