**1. Introduction**

68 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

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phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. *Handb. Exp.*  Cigarette smoking is clearly associated with the development of chronic airway obstruction pulmonary disease and is responsible for 80–90% of cases. However, only 15–20% of heavy smokers develop clinically significant airflow obstruction. In the rest pulmonary function remains within normal limits. Besides the risk factors that are involved in airway obstruction, the genetic predisposition is also considered a key factor. It modulates lung's response to cigarette smoke inhalation and the development of airway obstruction. In addition to smoke induced emphysema, genetic susceptibility leading to α1-antitrypsin deficiency is associated with the propensity for the development of early-onset, familial emphysema. Thus both environmental and genetic factors contribute to the pathogenesis of emphysema.

The molecular basis for tobacco smoke-induced emphysema is poorly understood. To thoroughly unravel the cellular and molecular events or signaling pathways that may contribute to the pathogenesis of smoke-induced emphysema or COPD, gene expression profiling - serial analysis of gene expression (SAGE) and microarray analysis as well as proteomics have been recently applied. The gene expression profiles of lung tissues from control smokers (GOLD-0) and moderate (GOLD-2) COPD smokers identified numerous classes of genes, the expression of which is altered in COPD patients. These include genes encoding molecules for signal transduction, receptor function, growth factor, nuclear chromatin and DNA binding, adhesion and cytoskeleton, metabolism, matrix, cell cycle, and oxidative stress such as HSP70 protein, heme oxygenase (decycling) 1 (HO-1). The data from proteomics also confirms a large number of proteins related to cigarette smoke induced endoplasmic reticulum stress, repair/injury proteins, heat shock proteins, apoptosis and cell cycle responsible molecules.

COPD is obviously a disease of imbalance of proteins - oxi/antioxidant, protease/ antiprotease, apoptosis/proliferation, acetylases/deacetylases, that can no longer perform their proper function to keep the homeostasis in the new environmental settings of the oxidative stress.

Molecular chaperones provide the functional activity of proteins, they counteract the formation of abberantly folded polypeptides and allow their correct refolding under stress

Chronic Obstructive Pulmonary Disease - Chaperonopathology 71

In conclusion normal chaperones, particularly cell stress proteins are important in cell physiology at all ages. They are responsible for protein folding, functioning and homeostasis and play critical roles as major cellular anti-stress and anti-disease mechanism. Defective chaperones are most probably an additional factor, accompanying the development and progression of senescence and age-associated diseases (neurodegenerative, cancer,

In the current chapter we shall represent COPD as a chaperonopathy (proteinopathy). We shall concentrate on the current data from research studies, concerning the molecular pathology of COPD, studies that are shedding light on the participation of stress molecules in COPD initiation and progression. We shall also comment the relation of chaperones to already known pathological mechanisms, their clinical application as diagnostic markers for

All organisms respond to potentially harmful environmental factors by an up-regulation of heat shock protein expression. Cell stress or heat shock proteins were first discovered in 1962 by Ritossa who observed a pattern of Drosophila salivary gland chromosome puffs induced under transient exposure to high temperature. It was subsequently described that these highly conserved group of proteins could be induced by many other stress factors. Mammalian heat shock proteins are classified into two groups according to their size: high molecular weight heat shock proteins (HSP) and small HSP - sHSP. The first group includes three major families: HSP90, HSP70 and HSP60. Some of these proteins are constitutively expressed (in-house chaperones), whereas the expression of the others is induced by stressful conditions. High molecular weight stress protein are ATP-dependent chaperones and require co-chaperones to perform their ATP-binding and modulate their conformation. In contrast sHSP are ATP-independent. Heat shock proteins are expressed in both normal

1) facilitating the proper folding of nascent proteins in cytosol, endoplasmatic reticulum, mitochondria; 2) import of proteins into cellular transport; 3) prevention of protein aggregates, refolding of denatured proteins; 4) degradation of unstable proteins; 5) control

HSP also participates in the intracellular transport and have been implicated in the loading of immunogenic peptides in histocompatibility complexes (MHC) in the T-cell

The HSP70 family is the most highly conserved and best studied class of HSP. Human cells contain several HSP 70 family members – constitutively expressed, inducible, mitochondrial – HSP75, and GRP78, localized in the endoplasmatic reticulum. Under normal conditions HSP70 proteins function as ATP-dependent chaperones, assisting the folding of newlysynthesised proteins, participating in intracellular transport of proteins across cellular membranes. Under stressful conditions the synthesis of inducible HSP70 enhances the ability of cells to cope with the increased levels of denatured proteins. HSP70 blocks caspase-depedent and independent activation of apoptosis (Shi et al,1992; Murakami et al,

atherosclerosis, COPD) most of which are aggrevated by stress.

COPD, as well as markers for NSCLC early detection.

**2. Cell stress or heat shock proteins** 

and stress conditions and are responsible for:

**2.1 High molecular weight heat shock proteins** 

of apoptosis.

presentation.

recovery. Chaperones are responsible for protein folding and allow the functional state of cells to be maintained, by preventing irreversible protein unfolding and aggregation. Numerous studies, over the last decade have investigated the structural and functional characteristics of molecular chaperones, classifying them in families based on size, structure and activity. Today there are more than 25 families of molecular chaperones, with more than 100 proteins participating in the folding events in the mammal. These include a group of proteins, known as heat shock or cell stress proteins.

Heat shock or cell stress response is one of the most evolutionary conserved protective mechanisms in cells. It is stimulated under ''stress'' (thermal, metabolic, oxidative, etc), when the conditions of the cell environment are deleterious and alter the protein folding and their proper biological activity. Cell stress involves the temporary modification of gene expression and synthesis of different heat shock protein family members. They help the cell and the organism to cope with environmental or physiological stress. Some of the heat shock proteins are constitutively expressed in non-stressed conditions and act as intracellular chaperones towards fundamental cellular processes – cytoskeletal architecture, mutation masking, protein transport, translation regulation, intracellular redox homeostasis, protection against spontaneous or stimulated programmed cell death - apoptosis. Others are synthetised in response to stress to prevent protein aggregation, refold damaged proteins. Hеаt shock proteins could also participate in the protein triage and modulate the ubiquitin – proteasome pathway, promoting the degradation of irreversibly denatured proteins.

While the cellular protein management of heat shock response and stress proteins is well described their role in the immune/inflammatory responses in multicellular organism is still elusive. As an anti-inflammatory effector the heat shock proteins influence cytokine signal transduction and gene expression by inhibiting the translocation of the transcription nuclear factor kappa B (NF-kB) to the nucleus. In this aspect they regulate the synthesis of inflammatory mediators. As proinflammatory mediators, necrotic and non-necrotic release of constitutively expressed or stress induced heat shock proteins, into the extracellular environment, produce a multifaceted immune/inflammatory response. They activate immune effector cells and stimulate cytokine release. Therefore the ability of heat stress response to modulate inflammation is an important aspect of a variety of pathophsysiological states, characterized by dysregulated inflammatory response.

Cell stress proteins are reported to be positively correlated to longevity and capacity for mounting a cell stress response, implying the fact that chaperones are essential adaptive mechanisms for survival. Unfortunately chaperone levels generally decrease or become functionally incompetent with age. The accumulation of misfolded proteins that occurs with senescence results in a chaperone deficiency and leads to the onset of degenerative or age related diseases. A shift in the balance between misfolded proteins and available free chaperones in ageing organisms can bring about defects in signal transduction, protein transport, cellular organization and immune functions.

Age-related post-translation modifications of proteins can seriously curtail or change their functions and thus give rise to proteinopathies of ageing, a hallmark of senescence at molecular level. A normal set of chaperones would potentially prevent the deleterious effect of proteinopathies. However chaperones also are being modified with the passage of time. These acquired chaperonopathies are likely to contribute significantly to senescence and lower the quality of life in the elderly.

recovery. Chaperones are responsible for protein folding and allow the functional state of cells to be maintained, by preventing irreversible protein unfolding and aggregation. Numerous studies, over the last decade have investigated the structural and functional characteristics of molecular chaperones, classifying them in families based on size, structure and activity. Today there are more than 25 families of molecular chaperones, with more than 100 proteins participating in the folding events in the mammal. These include a group of

Heat shock or cell stress response is one of the most evolutionary conserved protective mechanisms in cells. It is stimulated under ''stress'' (thermal, metabolic, oxidative, etc), when the conditions of the cell environment are deleterious and alter the protein folding and their proper biological activity. Cell stress involves the temporary modification of gene expression and synthesis of different heat shock protein family members. They help the cell and the organism to cope with environmental or physiological stress. Some of the heat shock proteins are constitutively expressed in non-stressed conditions and act as intracellular chaperones towards fundamental cellular processes – cytoskeletal architecture, mutation masking, protein transport, translation regulation, intracellular redox homeostasis, protection against spontaneous or stimulated programmed cell death - apoptosis. Others are synthetised in response to stress to prevent protein aggregation, refold damaged proteins. Hеаt shock proteins could also participate in the protein triage and modulate the ubiquitin –

proteasome pathway, promoting the degradation of irreversibly denatured proteins.

pathophsysiological states, characterized by dysregulated inflammatory response.

transport, cellular organization and immune functions.

lower the quality of life in the elderly.

Cell stress proteins are reported to be positively correlated to longevity and capacity for mounting a cell stress response, implying the fact that chaperones are essential adaptive mechanisms for survival. Unfortunately chaperone levels generally decrease or become functionally incompetent with age. The accumulation of misfolded proteins that occurs with senescence results in a chaperone deficiency and leads to the onset of degenerative or age related diseases. A shift in the balance between misfolded proteins and available free chaperones in ageing organisms can bring about defects in signal transduction, protein

Age-related post-translation modifications of proteins can seriously curtail or change their functions and thus give rise to proteinopathies of ageing, a hallmark of senescence at molecular level. A normal set of chaperones would potentially prevent the deleterious effect of proteinopathies. However chaperones also are being modified with the passage of time. These acquired chaperonopathies are likely to contribute significantly to senescence and

While the cellular protein management of heat shock response and stress proteins is well described their role in the immune/inflammatory responses in multicellular organism is still elusive. As an anti-inflammatory effector the heat shock proteins influence cytokine signal transduction and gene expression by inhibiting the translocation of the transcription nuclear factor kappa B (NF-kB) to the nucleus. In this aspect they regulate the synthesis of inflammatory mediators. As proinflammatory mediators, necrotic and non-necrotic release of constitutively expressed or stress induced heat shock proteins, into the extracellular environment, produce a multifaceted immune/inflammatory response. They activate immune effector cells and stimulate cytokine release. Therefore the ability of heat stress response to modulate inflammation is an important aspect of a variety of

proteins, known as heat shock or cell stress proteins.

In conclusion normal chaperones, particularly cell stress proteins are important in cell physiology at all ages. They are responsible for protein folding, functioning and homeostasis and play critical roles as major cellular anti-stress and anti-disease mechanism. Defective chaperones are most probably an additional factor, accompanying the development and progression of senescence and age-associated diseases (neurodegenerative, cancer, atherosclerosis, COPD) most of which are aggrevated by stress.

In the current chapter we shall represent COPD as a chaperonopathy (proteinopathy). We shall concentrate on the current data from research studies, concerning the molecular pathology of COPD, studies that are shedding light on the participation of stress molecules in COPD initiation and progression. We shall also comment the relation of chaperones to already known pathological mechanisms, their clinical application as diagnostic markers for COPD, as well as markers for NSCLC early detection.
