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July - September 2007: 
Volume 20, Issue 3

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Immunological Mechanisms in the Lung
Abstract
SUMMARY. The lung is directly and continuously exposed to the environment and has therefore developed strong defense mechanisms, which, as those of other organs, include innate and adaptive immune responses. Mechanical barriers, secretions of the bronchial mucosa, antimicrobial constituents of the blood, such as the complement system, and the leukocytes and phagocytes of the pulmonary system are all part of the innate defense. Adaptive immunity is deployed through delayed mechanisms, which are mediated mainly by T-cells, B-cells and the antibodies they produce. Adaptive immunity is specific for each virulent factor; it leads to the development of immune memory and therefore leads to successful and rapid response against that specific pathogen in future encounters. The balance between all these immune mechanisms is crucial for the deployment of a successful defense against infectious agents, cancer cells and autoimmune disorders, and for minimization of collateral lung tissue damage. Disorders of immune response may occur, leading either to reduced response and immune deficiency (serious infections) or to overreaction of the immune response, with allergy or autoimmune disease. Such disorders can characteristically be observed in diseases such as bronchial asthma, pulmonary emphysema, granulomatous inflammation, idiopathic pulmonary fibrosis and acute respiratory distress syndrome. Pneumon 2007; 20(3):274-278
Full text
Introduction

The environment that surrounds us contains thousands of microorganisms and other factors that can be harmful to health or even life threatening. In order to survive, we must be able to defend ourselves against these agents; this ability is called immunity. Most microorganisms encountered by a healthy individual on a daily basis are detected and destroyed within 0-4 hours by mechanisms that are not antigen specific; these immune mechanisms as a whole represent innate immunity. If a pathogen bypasses this first line of defense, a special antigen specific immune response will be deployed, which is directed specifically against the corresponding pathogen; this type of immunity constitutes adaptive or specific immunity. Special “memory”cells also develop in parallel, which contribute to a faster immune response in the event of a future infection by the same pathogen. The combination of innate and adaptive immunity provides a very effective defense system. The lung in particular has very strong defense mechanisms since, in contrast to other internal organs, it is exposed to the environment directly and continuously.

INNATE (NON-SPECIFIC) IMMUNITY

The epithelial surfaces of the body (skin and mucous membranes) keep pathogens away, as they provide mechanical, chemical and biological barriers that function as the first line of the body’s defense against infection. Epithelial cells are joined together with tight junctions to constitute mechanical barriers that prevent the passage of invading organisms. In the lung, the constant movement of the cilia1 and production of mucus contribute to the removal of the pathogens. Epithelial cells produce chemical barriers, such as, the low pH gastric secretions and gastrointestinal enzymes in the gastrointestinal tract, and the antimicrobial peptides2, chemokines, cytokines, protease inhibitors and opsonins produced by the respiratory epithelium. The normal flora of the skin and mucosa provides an antimicrobial barrier that competes with pathogenic bacteria for nutrients or attachment to the epithelium. Bacteria and antigens that penetrate these epithelial barriers3 encounter two direct lines of defense provided by the innate immunity. The first of these is the presence of several components in the blood that attach to pathogens, causing their destruction (humoral barrier of innate immunity), including complement, lysosymes and many peptides that deactivate various kinds of bacteria. The second line of defense is the non-specific recognition and phagocytosis of the pathogens by leukocytes and phagocytes that are present in or move into the infected tissue. Cells that contribute to innate immunity and lead to pathogen destruction are derived from myeloid progenitors, and are the following: neutrophils, monocytes and tissue macrophages, granulocytes (eosinophils, basophils, mast cells) and natural killer (NK) cells.

ADAPTIVE IMMUNITY

Innate immunity is very important since it constitutes the initial rapid reaction of the organism to any pathogen that enters the lung. However, innate immunity mechanisms are not always sufficient, and are supplemented by adaptive immunity, which is mediated through the lymphocytes. The deployment of adaptive immunity takes several days and depending on the type of lymphocytes involved it can be divided into cell-mediated or T-cell immunity and humoral or B-cell immunity. In order to multiply and differentiate into effector cells, the lymphocytes must first come into contact with and recognize their corresponding specific antigens, a process named antigen presentation.

Antigens

The term antigen refers to all chemical compounds that are able to stimulate the cells of the immune system and evoke a specific immune reaction. This reaction manifests itself through the production of soluble substances (antibodies) by B lymphocytes, or the deployment of cellmediated reactions by T lymphocytes, or both. Antigens are usually molecules of large molecular weight; proteins or polysaccharides. On their surfaces they exhibit specific aminoacid or sugar sequences, respectively, which are selectively recognized by cell receptors or antibodies. These antigenic determinant sites are called epitopes. Each antigen can have one or more different epitopes.

Major Histocompatibility Complex (MHC) and Antigen Presenting Cells (APCs)

The major histocompatibility complex (MHC) consists of a group of proteins found on the cell surface that help the immune system to recognize foreign (non-self ) antigens. The MHC complex is also known as HLA complex (human leukocyte antigens) since the MHC antigens were first recognized on white blood cells in subjects who had experienced allograft rejection (specifically, T lymphocytes responding to the foreign major histocompatibility complex of the graft). The MHC molecules help T lymphocytes to recognize infected cells by presenting antigens on their surface that originate from the intruder. Without the MHC complex, antigen presentation to T cells would never happen and there would be no immune response. There are two types of MHC molecules, class I and class II, which are coded on the same locus of chromosome 6. Although they have similar structures, the two MHC class molecules have distinct functions. Class I MHC molecules are located on the membrane of almost all nucleated cells and present “endogenous” antigens (i.e. antigens originating from intracellular bacteria, viruses or cancer cells) to cytotoxic T lymphocytes (CD8+ T cells). Cells that have class I molecules on their surface are called non-professional APCs. Conversely, class II MHC molecules are found only on B lymphocytes, macrophages and some other antigen presenting cells such as dendritic cells, and present “exogenous” antigens (i.e. phagocytosed fragments of bacteria or viruses) to helper T lymphocytes (CD4+ T cells). Dendritic and Langerhans cells are capable of “internalizing” an antigen, by means of phago- or endocytosis, and then presenting it, which is why they are also known as professional APCs.

INFLAMMATION AND IMMUNE RESPONSE IN THE LUNG


During pathogen invasion, the basic aim of body defense is destruction of the pathogen and control of the infection. Bacteria that overcome the physical, chemical and antimicrobial barriers and enter into the body for the first time are subject to humoral attack by the complement and many enzymes in the blood (defensins4, etc.), and to cellular attack by the phagocytic macrophages and neutrophils of the innate immune system.

The complement system consists of about thirty proteins that are produced in the liver, in monocytes and in macrophages. Complement proteins circulate in the blood in an inactive form and can be triggered by components of pathogen cell surfaces or by antigen-antibody complexes. This dual complement component activation results in a reaction cascade where each component activates the next molecule in line. When triggered by components on the pathogen surface, the binding of complement component C3 to pathogen surface carbohydrates causes serial activation of other components up to component C9. This pathway of complement activation is called alternative and includes (in a series) components C3, C5, C6, C7, C8 and C9 as well as proteins P, B and D. When triggered by antigen-antibody complexes, serial activation of the complement components is triggered by binding of the antigen-antibody complexes with component C1q. Serial activation of other components continues up to the final component C9. This pathway of complement activation is called classical; it serially involves components C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, C9, and is a part of specific immunity. The main outcome of these processes is the formation of a protein (C3b) that is attached to the pathogen cell surface in a process called opsonization. Opsonized cells (C3b-coated) are recognized and phagocytosed by macrophages and neutrophils that bear C3b receptors. In addition, complement components act as inflammation mediators, recruit phagocytes (C4a+, C3a, C5a) and induce vasodilatation and increased vascular permeability, causing redness and oedema at the site of infection. Complement activation can also result in the formation of a membrane-attack complex (MAC) that causes direct lysis of certain pathogens (C5B, C6, C7, C8, C9). Finally, complement contributes to the removal of antigen-antibody complexes from the body.



Tissue macrophages5 are the main phagocytes of the body. They are scattered throughout the tissues and in the alveoli in the lung (alveolar macrophages) and they are the first line cells that recognise and digest invading pathogens. They bear pattern recognition receptors (PRRs)6,7 that identify similar, non specific, patterns on the surface of pathogens – the pathogen associated molecular patterns (PAMPs)8,9, such as receptors (CD14, CD13) for Gram negative bacteria lipopolysaccharides (LPS), macrophage mannose and glycan receptors for Gram positive bacteria, etc. Macrophages can also engulf, digest and present antigens coated with antibodies or complement components, through specific surface receptors. Their third main function is the secretion of several mediators that orchestrate inflammatory responses. The cytokines they secrete (IL-1, IL-8, IL-6, IL-12, TNF-a) induce increased antibody production by B cells and the differentiation of CD4+ T cells into Th1 or Th2, whereas chemokines promote the recruitment of other types of inflammatory cells to the site of infection (chemotaxis).

The major role of chemokines10 is chemotaxis, which oris the migration of cells to the sites of infection. There are about 80 chemokines, categorized into four families, CXC, CC, C, CXXXC. The CXC family, which includes IL-8, MIP-2, GRO, ENA-78 and NAP-2, promotes the activation and migration of neutrophils. The CC family, which includes MCP-1, MCP-2, MCP-3, RANTES, MIP-1a and MIP-1b, promotes the migration of macrophages, lymphocytes, eosinophils, basophils and mast cells. Lymphotactin is the only C chemokine, and fractakline is the only CXXXC chemokine to be identified so far.

When the microbial load is small, alveolar macrophages destroy pathogens efficiently through phagocytosis. However, when the microbial load is heavy or consists of resistant pathogens (e.g. encapsulated Gram negative bacteria such as K. Pneumoniae), tissue macrophages are inadequate and cannot respond effectively to infection, in which case, they secrete cytokines that recruit neutrophils11 and other inflammatory cells. The migration of leukocytes (neutrophils, and eosinophils in the case of allergens or parasitic infections), takes place according to a process called recruitment12. Circulating cells of innate immunity (e.g. eosinophils, neutrophils) move along the vascular endothelium (rolling) through reversible, weak interactions with its components (e.g. selectines13), which are unable to anchor the cells against the shearing force of the blood flow. Chemokines (e.g. Eotaxin, RANTES, ΙL-8) produced by damaged tissue or other inflammatory cells in sites of inflammation give rise to expression of extra adhesion molecules, such as ICAM-114 on the endothelium, and its receptors on the leukocyte (LFA-1, Mac-1) (activation). These changes cause tight binding between the leukocyte and the endothelium and contribute to extravasation of leukocytes (diapedesis) into the tissue. Finally, the leukocytes migrate along a concentration gradient of chemokines to the site of infection. Neutrophils are the first cells appearing at sites of tissue damage or infection and destroy the pathogens mainly by phagocytosing them. Similarly to macrophages, neutrophils carry PRRs and complement receptors. They excrete many enzymes such as lysosymes, proteases, defensines, hydrogen peroxide etc., that destroy the pathogens, but which also cause tissue damage. Neutrophils are important cells in combating infection, and also in the pathophysiology of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD).

Natural killer (ΝΚ) cells are important for the rapid defense of the host, acting by destroying cancer cells15 and cells infected by viruses16. They can rapidly produce cytokines that activate T cells, macrophages and B cells, providing a link between innate and adaptive immunity. They also play an important role in the balance of inflammatory signals, as they express many activating and inhibiting receptors. One of these is receptor Ly49. When this receptor binds to the surface of healthy cells that carry normal MHC class I molecules, NK activation and the subsequent cell lysis is inhibited. Altered or absent MHC class I molecules on virus infected or cancer cells cannot stimulate a negative signal through Ly46. In this case, NK cells are activated by a NKR-P1 receptor that leads to the release of lytic granules and to the apoptosis of the target cells.



Mast cells17 play a major role in type I hypersensitivity reactions of the innate immunity system, as their activation causes increased blood flow, increased vascular permeability and fluid extravasation into the surrounding tissues. They bear FcεRI receptors that have high affinity for IgE antibodies, which they therefore bind onto their surface. When the cell-bound IgE is cross-linked (bridging) by allergens, the mast cells release histamine, serotonin, tryptase, prostaglandins and cytokines (IL-4, TNF-α), which cause the acute phase of allergic reactions, e.g. acute asthmatic attack, rhinitis or even anaphylaxis. In asthma patients, mast cells are important in remodeling, as tryptase stimulates the proliferation of fibroblasts.

The adaptive immune response and the subsequent immunological memory is initiated when T cells encounter specific antigens and become activated in peripheral lymphoid organs18. Antigens are transported from the sites of inflammation to the peripheral lymph nodes, where they are taken up by professional antigen-presenting cells (macrophages, dendritic cells, B cells) and are presented to naive (undifferentiated) T cells. Naive T cells recirculate in the venules of the cortex of peripheral lymphoid organs and enter the lymphoid tissue following a process similar to that of neutrophil recruitment. T cells that do not encounter a specific antigen leave the lymph nodes and return into circulation through the lymphatics, while T cells that encounter their specific antigen are activated to proliferate and differentiate into effector T cells.

The activation process for T cells is generally similar for both helper T (Th) cells and cytotoxic T (Tc) cells. The first step is taken when circulating T lymphocytes are activated in local lymph nodes. This begins when a non-differentiated T cell, also known as “naive” T cell, encounters its specific antigen on a professional antigen presenting cell. Every naive lymphocyte that enters the circulation has receptors (TcR) of unique specificity. The activation starts with the interaction between the TcR-CD3 and antigen-MHC molecule complexes on the surface of the antigen presenting cell. This interaction increases IL-2 secretion by the T cell, and IL-2 receptor expression on its surface. IL-2 acts as an autocrine cytokine, inducing the development and multiplication of the cell line that originates from the specific T lymphocytes (clonal expansion). Other naive T cells do not express IL-2 receptors on their surface and cannot be induced by this process. CD4 helps the activation of the TcR complex, acting as a coreceptor to amplify the signal generated by the TcR. Other helper molecules, such as CD4519, CD2820 and CD2 may possibly be involved in the process. At the same time, the APC generates a co-stimulatory signal, possibly through Β721 molecules. This activation process is similar for both CD4+ and CD8+ T cells and all professional APCs.



Activated CD4+ T cells are differentiated into inflammatory Th1 or helper Th2 lymphocytes, the roles of which differ22. Th1 cells secrete IL-2, TNF-β and IFN-γ and are very effective in activating macrophages, and Th2 lymphocytes secrete mainly interleukins IL-4, IL-5 and IL-10, which help B lymphocytes to produce antibodies. This stage of T cell differentiation is therefore vital as it determines the type of immune response that will prevail, humoral or cell mediated23. This does not occur with CD8+ T lymphocytes, which are predetermined to evolve into cytotoxic cells. Although the factors that predetermine the differentiation course of naive activated T cells is not yet fully known24, there are indications that the type and concentration of the pathogens, the APC type and the cytokines it secretes, the cytokines that are present and the chemical affinity between the TcR and MHC complexes are all key components of the process.

The course of naive T cell differentiation and the prevalence of either the Th1 or the Th2 response have an impact on the clinical outcome. For example, when the pathogen is a Koch bacillus, differentiation of T lymphocytes is driven towards the Th1 direction and the prevalence of cell-mediated immune response, due to the nature of the antigenic stimulus. This response is accompanied by the secretion of IL-2, IL-12, IFN-γ and macrophage activation25. Macrophages are activated against the bacillus-infected cells, resulting in the characteristic granulomatous disease known as tuberculosis. When the initial antigenic stimulus comes from an allergen, the immune response is activated towards the Th2 pathway and interleukins IL- 4, IL-5 and IL-10 are secreted. This results in eosinophilia and Ig-E dependant processes associated with allergic diseases and asthma.

CD8+ cytotoxic T cells (Tc) are very important for the defense of the lung against several intracellular pathogens, mainly respiratory viruses. They kill infected cells that present the corresponding antigens on MHC class II molecules by secreting a number of cytotoxins such as perforin. Thus, they remove all pathogen replication loci, reducing, for example, the viral loads. At the same time, CD8+ T cells can induce apoptosis26,27 by binding to target cells with the help of Fas28, a binding molecule located on their surface. Tc cells can also produce IFN-γ which blocks viral replication29, induces the expression of MHC class I molecules and activates macrophages. Cytotoxic cells kill infected targets with great precision30 and protect neighboring healthy cells to a great extend, minimizing collateral damage.



The mechanisms described concerning the activation and differentiation of T lymphocytes are all part of the cell-mediated specific immunity. Humoral immunity is based on B lymphocyte activation. When an antigen binds to a B cell receptor (BcR), a signal is transmitted, intracellularly. As with T lymphocytes, B lymphocyte activation needs two stimuli acting simultaneously. The source of the second stimulus depends on the type of antigen. There are antigens that need the help of helper T lymphocytes to activate B cells; these are the so-called thymus-dependent antigens31. On the other hand, structural elements of many microbes, such as the bacterial polysaccharides, are thymus-independent, meaning that they can stimulate B lymphocytes directly to produce antibodies in the absence of T cells32.

Activation of B lymphocytes by T helper cells occurs in a way similar to the activation of naive T cells. When a Th2 cell encounters its specific antigen on the surface of a B cell, it binds to it via the TcR and starts producing IL-4 and CD4033. The T cell then reorientates its cytoskeleton so that all cytokines are secreted towards the B cell. CD40 is a stimulatory molecule for B lymphocytes34, while IL-4 and other interleukins such as IL-5 and IL-6 are secreted by T helper cells and bound by special receptors on B cell membrane. This leads to the multiplication and differentiation of B cells to plasma cells that secrete free antibodies against that specific antigen. The binding of the antibody to its specific antigen can be compared, in a simplified manner, to the way the key (antigen) fits into its lock (antibody). Every antibody has a unique arrangement in space, so that it contains areas of high affinity towards its specific antigen. Binding to antibodies neutralizes viruses35 and targets pathogens to be destroyed by macrophages and the complement system. Antibodies attaching to the surface of the pathogen (bacterium) can exert the following effects: stop it from binding onto healthy cells36, induce its phagocytosis37 or activate the complement system to increase opsonization and bacterial lysis38.



IMMUNE RESPONSE DISORDERS


Immune responses aim at an effective defense against pathogens. Inflammatory reactions contribute to the uptake, presentation and destruction of pathogens. This procedure is quite precise, so that destruction of pathogens and therefore effective immunity defense is achieved with minor effects in the surrounding tissues from the pathogens or the inflammatory cells. However phagocytes and granulocytes cause local tissue damage by secreting a number of enzymes. This damage needs to be repaired. The repair process may lead to the chronicity of these effects in the lung, with structural changes39 such us intra-alveolar septum destruction, airway stenosis, vascular endothelium thickening, bullae formation, etc. Such examples of chronic damage in the respiratory system are remodelling in asthma, emphysema changes and airway stenosis in COPD, scar formations in sites of TBC infection and pulmonary fibrosis. The suppression of such events is crucial, as the lung is a vital organ and damage, even if only of a small extent, can cause functional disorders and permanent disability.

For this reason the specificity of immune responses, the balance between inflammation and tolerance-healing reactions (intrinsic and extrinsic regulation of immunity) are crucial for the maintenance of normal tissues and the avoidance of chronic damage.

The balance between inflammatory and tolerance reactions is achieved by intrinsic and extrinsic regulation of immune responses. Intrinsic regulation of immunity is crucial for the suppression of an undesirable inflammatory cascade. Feedback inhibition reactions are responsible for the apoptosis of effector T Cells40 and the reduction of circulating antibodies after the clearance of the pathogen. Th1 and Th2 subpopulations of CD4+cells can downregulate each other through the secretion of cytokines. Thus, TGF-β and IL-10 produced by Th2 cells act on macrophages that in turn inhibit Th1 activation, whereas Th1 cells secrete IFN-γ that suppresses Th2 proliferation41. Moreover, activated CD8+Tcells secrete cytokines that regulate Th1 and Th2 reactions. The Complement system42 has regulatory proteins that protect host cells and prevent its continuous activation. The extrinsic regulation of immune responses is the aim of treatment in the majority of pulmonary diseases. The widely used corticosteroids are powerful inhibitors of inflammatory reactions43. They promote lymphocyte apoptosis and they suppress the inflammatory actions of leukocytes. Mast cell stabilizers, antagonists for receptors, mediators and antibodies, antioxidants, cytotoxic drugs and immunotherapies aiming at the immunomodulation and suppression of immune responses are also used in many pulmonary diseases.

The interventions that suppress inflammatory reactions often have a common pathway, i.e., the programmed death of inflammatory cells, namely apoptosis44. Furthermore, apoptosis is necessary for the destruction of intracellular pathogens that are not accessible to circulating antibodies, and for repair of tissue damage without scar formation. Cytotoxic T cells45 can induce apoptosis of infected cells by either releasing lytic granules or activating membrane molecules. Apoptosis is crucial in the defense and regulation of inflammatory reactions, but it is implicated in the pathophysiology of certain diseases, such as emphysema.

EMPHYSEMA

Emphysema is characterized by loss of elasticity of lung tissue, destruction of structures supporting the alveoli and destruction of the capillaries feeding the alveoli. This leads to collapse of small airways during expiration and obstructive lung disease. The pathogenesis of emphysema remains an enigma, although the hypothesis of proteaseantiprotease imbalance is popular46. Briefly, according to this theory, activated alveolar macrophages release elastase and increase their elastolytic activity47 under the influence of several stimuli, the most important of which is smoking. Many smokers, however, never exhibit emphysema, suggesting that, apart from the environment, genetic factors also contribute to the pathogenesis of the disease. Many studies support the theory that the damage to the lung parenchyma and alveolar septa occurring in emphysema might be a result of gradual loss of the endothelial and epithelial cells of the lung due to abnormal apoptosis48. This disorder seems to correlate directly with the decreased expression of vascular endothelial growth factor (VEGF) in the lung49.

GRANULOMATOUS INFLAMMATION

Another case where the immune system overreacts against a pathogenic stimulus resulting in clinical disease is granulomatous inflammation. It is basically a type IV hypersensitivity reaction, which starts when stimulated T cells are exposed to their specific antigenic peptides, when the microbes effectively resist macrophages. In the long term this results in the accumulation of macrophages at the site of inflammation. Granulomatous inflammation is a distinct form of chronic inflammation characterized by a central area of macrophages surrounded by activated T lymphocytes. This pathohistological pattern is called granuloma. Modified gigantic macrophages (epithelioid macrophages)50 that have engulfed each other are usually located in the centre of such granulomas, to deal with the pathogens that resist being lysed. Granulomas are observed in a few pathological situations, with tuberculosis being the major granulomatous disease. In tuberculosis, it is quite common for the centre of the granuloma to become isolated, resulting in local necrosis, due to the lack of oxygen and the cytotoxic effects of activated macrophages. As the dead tissue in the centre of the granuloma resembles cheese, this process is called caseation. This process is a key feature of tuberculosis. Recognizing a granuloma is very important, because the diseases it occurs in, although limited in number, may be life threatening. This type of hypersensitivity is a major defense mechanism against a variety of intracellular pathogens i.e. mycobacteria, fungi and certain parasites, but it can also take place in allograft rejection and immunity against tumour cells. Sarcoidosis is a systemic granulomatous disease of unknown aetiology, usually affecting the lungs and characterized by granulomas with very little or no caseation. In the case of immunosuppressed patients (e.g., AIDS patients), the immune response against intracellular pathogens is diminished. Microbes are ingested by macrophages but not killed since CD4+ T lymphocyte levels are very low. In this case no granulomas are formed, instead what is observed are small gatherings of non-activated macrophages. Other diseases that feature granulomatosis are Crohn’s disease, berylliosis, syphilis, Wegener’s granulomatosis and Churg- Strauss syndrome.

BRONCHIAL ASTHMA

Bronchial asthma is another disease related to a disorder of the immune response of the organism. Although several genetic factors have been implemented in the pathogenesis of the disease51, the effect of various environmental factors seems to be of greater importance. Especially in extrinsic allergic asthma, the initial exposure to the allergen induces CD4+ T cells to produce and secrete interleukins 4 and 5, which in turn stimulate B cells to produce IgE, act as mast cell growth factors (IL-4) and mobilize/activate eosinophils (IL-5)52. IgE antibodies bind to specific receptors on the surfaces of mast cells and basophils53. Re-exposure to the same allergen results to its binding to mast cell IgE, which initiates a sequence of reactions on the mucosal surface, including degranulation of mast cells and the subsequent release of histamine and other mediators54, such as leukotrienes C4, D4, E4 and prostaglandin D2. These induce the bronchoconstriction, oedema and mucus oversecretion observed in the early phase of an asthma attack. The late phase that follows is characterized by additional recruitment of leukocytes (basophils, neutrophils and eosinophils) and aggregation at the site of inflammation, driven by cytokines such as IL-455, TNF-α56, leukotriene B457,58 and Eotaxin59. These cells release further cytokines, which amplify the initial immune response but also damage epithelial cells. The epithelial cells of the lung produce mediators such as endothelin and nitric oxide (NO)60 that can induce constriction and relaxation of the smooth muscle cells respectively. The subsequent loss of epithelial integrity in the lung caused by asthma may contribute to airway hyperresponsiveness (AHR). The chronic inflammation observed in asthma results in nonreversible changes in the airways (remodeling) 61, including epithelial damage, wall thickening62, mucus gland hyperplasia, increase in smooth muscle mass and collagen deposition. TGF-β63, along with other factors recently identified such as activin-A64 and osteopontin (Opn)65, seem to play a key role in the process of remodeling in asthma. Airway inflammation and remodeling are not directly proportional, and although it has been shown that the decrease of eosinophil levels correlates to a decrease of several markers of remodeling66, some patients with pronounced inflammation and frequent exacerbations do not exhibit remodeling on lung biopsy. Conversely, some patients with fixed airway obstruction and severe decrease in lung function have not presented with exacerbations67.

LUNG CANCER

Immune response disorders may be responsible for the development of malignancies, since one of the tasks of the immune system is the recognition and destruction of altered/malignant cells. Many malignancies such as lymphoma, leukemia and Kaposi’s sarcoma, appear in cases of immunodeficiency disorder. Cancer cells can escape immune surveillance in many ways68. Firstly they express novel antigens in low quantity, which therefore do not promote adequate immune response (i.e., low immunogenicity69). Secondly, the expression of tumour antigens changes due to frequent mutations (antigenic modulation), and finally tumours produce cytokines, such as TGF-β70, that inhibit T-cells directly. The body defense against these changes is achieved by two types of cells: Tc cells attack cancer cells that have adequate numbers of MHC molecules on their surface, whereas NK cells destroy cancer cells that have lost or altered their MHC molecules. There is a body of research on treatment of malignancies by activation of the immune system to induce adequate immune response against cancer cells. Concerning lung cancer, surface antigens from cancer cells have been used for the preparation of vaccines that stimulate the immune system to produce of cancer antigen specific antibodies. Numerous tumour cell surface antigens have been used, including carcinoembryonic antigen (CEA)71, which is found on the surface of up to 80% of NSCLCs and gangliosides (GM2, GD2, GD3)72, as cell surface targets for immunotherapy of SCLC73. Dendritic cells activated through incubation with fragments of NSCLC cells and presenting cancer cell antigens on their surface are used experimentally for the induction of T cell reactions against cancer cells74. Finally, recombinant humanized monoclonal antibodies (MoAb) against VEGF have been used (bevacizumab Avastin®), a factor produced by cancer cells that enhances angiogenesis and blood perfusion of the rapidly growing neoplastic tissue. Its use in NSCLC patients has a significant survival benefit, but with the risk of increased treatment-related deaths (mostly due to haemoptysis)75,76.

ACUTE RESPIRATORY DISTRESS SYNDROME

A typical example of the misbalance between inflammation and tolerance/healing reactions is the acute respiratory ddistress syndrome (ARDS)77. This syndrome results from a direct or indirect insult on the lung and is characterized by hypoxaemia, low respiratory system compliance, low functional residual capacity, diffuse radiographic infiltrates and increased alveolar epithelial permeability. The pathophysiology of the disease is obvious in cases of a direct insult, where toxic substances or pathogens damage the alveolar membrane causing oedema, collagen deposition, blood and inflammatory cell extravasation. In the case of an indirect insult, immune response disorders are responsible for the pulmonary lesions, which originate indirectly from mediators (cytokines, proteases, NO, oxidative agents e.g.) released by extrapulmonary foci into the blood, as in the case of peritonitis, pancreatitis and various abdominal diseases, causing microvessel congestion and interstitial oedema.

IDIOPATHIC PULMONARY FIBROSIS

Diffuse lung diseases and their common representative, idiopathic pulmonary fibrosis (IPF)78 are caused by deregulation of immune responses and apoptosis in the lung. It is believed that alveolar epithelial cells, as a consequence of injury by an unknown cause, may be the source of a number of fibrogenic cytokines such TGF-β1, PDGF, TNF-α, IL-1 and basic fibroblast growth factor. Release of these cytokines may result in fibroblast proliferation and migration to various sites in the lung, followed by differentiation of the fibroblast phenotype. These differentiated fibroblasts appear to be more resistant to apoptosis and demonstrate a heightened responsiveness to the cytokines mentioned earlier. These events would lead to prolonged retention of fibroblasts, continued connective tissue protein synthesis79 and formation of fibroblast foci, and finally, to established fibrosis.

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