**5. COPD – An accelerated lung ageing disease, chaperonopathy or proteinopathy?**

Ageing implies a certain period; the passage of time from conception till death. Senesence is a function of ageing and implies the molecular and cellular processes that accompany it. Senesence is the structural characteristics that appear as times goes by. They could either be physiological, or more often deleterious ones that occur in the organism after it has fully developed and affect its molecules, cells and tissues. A distinction should always be made between senescence and ageing, since the structural characteristic at molecular level do not always correspond to the age, depending on the "stress" conditions and the adaptive capacities of the organism.

Different organisms, particularly their cells are challenged to thrive to different environmental and emotional stress factors (physiological stress, emotional stress, oxidative stress, food deprivation, sleep deprivation, hypoxia, ischaemia, etc ) for one and the same period of time. They are trying to keep the balance, reaching the homeostasis and getting adapted to the new conditions that they are currently in. This is performed by the stimulation and engagement of a number of evolutionary developed and genetically predetermined pathways:1) inflammatory pathways; 2) unfolded protein response 3) heat shock response 4) ubiquitin proteasome system. The pathways are executed by an armamentarium of chaperones that " take care" and provide functionally available proteins. In case of failure the damaged proteins are cleared by another armamentarium that clear the cells from destructive components.

Chaperonology, the study of chaperones and HSP is emerging as a new area of physiology and molecular biology that could be of importance in both pathology and medicine. Defective chaperone function can contribute to the etiology of pathologic conditions, known as chaperonopathies. Chaperonopathies can be genetic or acquired. Usually the latter are described as quantitative variations in chaperone levels in tissue or body fluids that are accumulated as a result of posttranslational modifications. These variations and modifications have been described for the separate members of the HSP and their association with old age and age-related diseases have been largely reported. However data is scarce to demonstrate neither a direct link between a chaperonopathology and a definitive molecular or cellular characteristic, typical of senescence, nor to attribute certain chaperonopathy to a specific disease, associated with ageing.

Age-dependent damage to proteins is one of the primary molecular features of senescence. The appearance of age-related post-translational modifications of proteins – proteinopathies can seriously disturb or entirely change their cellular function, or make them immunogenic. The accumulation of modified proteins as time goes by could be attributed to several models:

diseases and the healthy smoking volunteers (p=0.007). In comparison there was not a significant difference between the COPD patients and those with inflammatory pulmonary diseases - (p=0.158). No relation was established between αB-crystalline plasma levels and

Authors concluded that αB-crystalline is not a specific diagnostic marker. It rather reflects

Ageing implies a certain period; the passage of time from conception till death. Senesence is a function of ageing and implies the molecular and cellular processes that accompany it. Senesence is the structural characteristics that appear as times goes by. They could either be physiological, or more often deleterious ones that occur in the organism after it has fully developed and affect its molecules, cells and tissues. A distinction should always be made between senescence and ageing, since the structural characteristic at molecular level do not always correspond to the age, depending on the "stress" conditions and the adaptive

Different organisms, particularly their cells are challenged to thrive to different environmental and emotional stress factors (physiological stress, emotional stress, oxidative stress, food deprivation, sleep deprivation, hypoxia, ischaemia, etc ) for one and the same period of time. They are trying to keep the balance, reaching the homeostasis and getting adapted to the new conditions that they are currently in. This is performed by the stimulation and engagement of a number of evolutionary developed and genetically predetermined pathways:1) inflammatory pathways; 2) unfolded protein response 3) heat shock response 4) ubiquitin proteasome system. The pathways are executed by an armamentarium of chaperones that " take care" and provide functionally available proteins. In case of failure the damaged proteins are cleared by another armamentarium that clear the

Chaperonology, the study of chaperones and HSP is emerging as a new area of physiology and molecular biology that could be of importance in both pathology and medicine. Defective chaperone function can contribute to the etiology of pathologic conditions, known as chaperonopathies. Chaperonopathies can be genetic or acquired. Usually the latter are described as quantitative variations in chaperone levels in tissue or body fluids that are accumulated as a result of posttranslational modifications. These variations and modifications have been described for the separate members of the HSP and their association with old age and age-related diseases have been largely reported. However data is scarce to demonstrate neither a direct link between a chaperonopathology and a definitive molecular or cellular characteristic, typical of senescence, nor to attribute certain

Age-dependent damage to proteins is one of the primary molecular features of senescence. The appearance of age-related post-translational modifications of proteins – proteinopathies can seriously disturb or entirely change their cellular function, or make them immunogenic. The accumulation of modified proteins as time goes by could be attributed to several

**5. COPD – An accelerated lung ageing disease, chaperonopathy or** 

hsCRP and MMP-9 levels respectively (p=0.91 and p=0,76)

oxidative stress, and inflammation that accompanies it.

**proteinopathy?** 

capacities of the organism.

cells from destructive components.

models:

chaperonopathy to a specific disease, associated with ageing.


Ignoring the dilemma, whether the chaperonapathies or the proteinopathies are first during the process of ageing, the immune system will inevitably response to what is going on in the organism. If this is the chaperonopathy 1) Chaperones could be spilled extracellularly as "danger" signals, activating the antigen-presenting cells; 2) chaperones could be associated with other peptides on the surface of cells announcing for a ''danger''cytotoxicity or; 3) chaperones can simply allow the accumulation of modified proteins that are accepted as self-antigenic.

If this is simply a proteinpathy as Kirkow assumes the defects cause inflammatory reactions, which can themselves exacerbate existing damage, so that inflammatory and antiinflammatory factors can play a part in modulating the outcome of the ageing process. Thus, age-associated inflammation/structural change is a failure of elimination and/or failure of repair (DNA, protein).

Ito and Barnes, 2009 define COPD as accelerated lung ageing disease. They find a lot of similarities between aged lung and COPD lung. These are not mere clinical characteristics – accelerated decline of lung function but a number of molecular ones.


Chronic Obstructive Pulmonary Disease - Chaperonopathology 87

Lung cancer is also a leading cause of morbidity and mortality in patients with COPD as 33% of patients died of lung cancer over a 14,5 year follow-up (Anthonisen et al, 2005; Yao et al, 2009). Furthermore ≈60% of patients, diagnosed with lung cancer have a spirometric evidence of COPD (Molina et al, 2008). NSCLC accounts for 85% of lung cancer cases in USA and the COPD related cancer type (squamous cell lung cancer) still represents the most common histological subtype of lung cancer in European men (Papi et al, 2004). Despite significant advances in diagnostic approaches, the pathology of lung cancer is still elusive and there has been little improvement in 5-year survival rates (≈ 15% overall; <14% among

Two of the leading causes morbidity and moratlity worldwide – COPD and lung cancer are due to the environmental risk factor and cigarette smoke exposure in combination with

There is a cascade of molecular events that mediate the transformation of a normal cell to a cancerous one. Several etiological factors and events are recognized as triggering mechanism of cancerogenesis – viruses, radiation, hereditary and non-hereditary mutations, carcinogenic compounds. Most tumors are formed by stepwise progression of normal cell into a cancer one by using alterations in cell physiology, described by (Hanahan and Weinberg, 2000) – self sufficiency in growth signals, insensitivity to growth inhibiton, evasion from apoptosis, limitless replicative senescence, sustained angiogenesis and tissue invasion and metastasis. Heat shock reponse participates in cancerogenesis of both up – and downregulation of specific heat shock proteins. Variations in HSP expression could be found in many tumors and preneoplastic lesions as well. At a histological level the transition from a normal tissue to tumor is accompanied by the increase in HSP expression. HSP are involved in the cancerogenesis and are up-regulated to protect cells from apoptosis and induce drug resistance. Their role in cancer cells is to protect other proteins against aggregation, to solubilize initial protein aggregates, to assist in folding of nascent proteins or refolding of damaged proteins; to target severely damaged proteins to degradation. Overexpression of HSP in cancer cells is beneficial to their survival because they inhibit apoptosis and induce drug resistance. They act as a double-side sword. Some of them - HSP90 maintains chaperoning function in a number of oncogenic molecules and promotes tumor survival. Others – HSP60,70 and HSP72 may sensitize cancer cells to immune attacks by two mechanisms. They may be expressed on tumor cell surface and enhance their recognition by NK-cells or induce antitumor immunity by HSP related tumor vaccines

Bonay et al, 1994 are the first to study the expression profile of HSP in the normal lung as well as the effect of cigarette smoke on their expression. They provide detailed description of HSP distribution in lung carcinoma, applying both immunohistochemical and immunoflourescent techniques for their investigation. In lung tissue from non-smokers, lung epithelial cells are positive for HSP90 and the inducible form of HSP70. There was also a weak expression of HSP60. Macrophages also expressed these HSPs but weaker in

males and <18% among females) (Youlden et al, 2008).

genetic predisposition.

**6.1 HSP and cancer** 

(Calderwood et al, 2006).

**6.1.1 HSP and non-small cell lung cancer** 

in healthy adults,(Kirkril et al, 2008) although this is still controversial (Nadeem et al, 2005).COPD patients also have reduced total antioxidant capacity. Furthermore, ferricreducing antioxidant power is lower in COPD patients, and it had a positive correlation with the severity of airways obstruction (FEV1 percentage of predicted).


Analysing the presented data we can assume that COPD could be regarded as a chaperonopathy (proteinopathy), as a model of accelerated ageing, in which the organism can not keep the homeostasis under the conditions of oxidative stress. The immune system is involved, but instead of restoring the balance it augments the oxidative stress, generating a large number of reactive – oxygen species. This leads to the accumulation of modified selfproteins that are recognized as antigenic. Autoimmunity occurs as an epiphenomenon. A vicious circle is created. The environmental and the inflammatory oxidative stress leads to the accumulation of modified proteins. Chaperones are additionally depleted or also modified. Ubiquitin proteasome system is overloaded or also modified.
