**7.3 Treatment**

92 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

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

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

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.

There is a lot of data about inflammatory and autoimmune (neurodegenerative, degenerative joint diseases, atherosclerosis, diabetes type I) diseases triggered as a result of

would be more reasonable to select patients considering phenotypes in COPD.

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

already irreversibly deteriorated.

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 from alteration?
