The immune response in the lung

The immune system can be divided into two types, the innate response and the adaptive response. The innate response is comprised of germ-line encoded components that provide an immediate "first-line" defence to continuously remove noxious influences (pathogens) or microorganisms faced on a daily basis. The “first-line” of defence involves physical barriers to infection that prevent any interaction between the pathogen and the host. The “second-line” of defence involves the action of phagocytic cells. This response can destroy any of these microorganisms within a matter minutes or hours following their entry into the body. It involves certain mediators that take part in this type of response that include histamine, prostaglandins, leukotrienes, platelet-activating-factor (PAF) and particularly interleukins.

This response often leads to inflammation (witnessed by oedema) and the accumulation of white blood cells at the site of entry. (Janeway et al., 2001).

31 Alternatively the adaptive immune response is the provision of long lasting and specific protection against formerly encountered pathogens, which takes days to develop, achieving specificity through somatic recombination and selection of pathogen (antigen) receptors. If any pathogens are not removed by the innate response then the adaptive response will be activated. This response ensures immunity to further illness following an initial infection caused by that same pathogen. This response is specific to the particular pathogen and involves several cell types, the most prominent being lymphocytes.

Lymphocytes can be divided into three different cell types; B cells, T cells and natural killer (NK) cells. The adaptive response consists an induction phase and an effector phase. During the induction phase both B and T cells recognise the pathogen through surface receptors.

Division of these cells occurs to produce a large colony of cloned cells that can recognise the pathogen. These cloned cells then form the effector response and have the ability to differentiate into plasma cells (B cells) that produce antibodies or take part in the cell-mediated response (T cells). Some cells become antigen-sensitive memory cells, such that if the same antigen enters the body there will be a greater immune response (Rang et al., 1999).

The immune response also includes the significant role performed by chemokines and cytokines. Their particular role is to attract specific inflammatory cells when activated, thus mediating the inflammatory response (Rang et al., 1999). Typically an inflammatory response is a positive response targeted at protecting the host’s normal biological functions;

however, chronic inflammation that is associated with disease can have a negative impact on the host.

32 1.3.2 Lung repair and fibrosis

The lung, with its massive surface area and unique gas exchange function remains the frontline of defence against harmful environmental pathogens/factors. Therefore, injury to large conducting airways through to terminal air exchange alveoli is a recurrent process over time for every living individual and related repair and remodelling processes are crucial in maintaining normal lung function (Strieter, 2008). There are a wide variety of epithelial cells lining the airway and alveolar surfaces to serve as the first line of defence against harmful foreign agents/pathogens. As described previously, this defensive approach includes mucus secretion, ciliary movement, electrolyte and fluid transportation across respiratory surface membranes and surfactant production. During lung injury, damaged epithelial cells are released from the lining surface, which leaves a bared epithelial surface with disrupted barrier function. In order to restore normal functions a regeneration process is initiated. In distal lung, resident progenitor cells inherited from developing lung cell lineages and/or recruited circulating stem cells migrate, proliferate, and differentiate to re-epithelialize the surface, and replace the original cell types and functions if the structural scaffold is not extensively damaged. The state of the underlying extracellular matrix may be crucial in guiding repair of injury, which may provide niches for appropriate cell expansion and differentiation.

Studies in lung injury-repair have identified changes in cell behaviour and gene expression that are indicative of specific developmental processes in the lung. However, lung repair has its own unique features in addition to these growth factors. For example, the involvement of pulmonary inflammation and the secretion of cytokines/chemokines related to the process.

The process of lung fibrosis may be regarded as an abnormal healing process related to failure of resolution of lung damage and restoration of normal structure (Strieter, 2008).

33 1.3.3 The cellular and inflammatory responses in COPD

Within the complex vapour and particulate matter that makes up cigarette smoke are more than 4700 various compounds (Ingebrethsen, 1986). Following cigarette smoke inhalation, this wide range of carcinogens and oxidants are believed to exert biological effects by stimulating the epithelial cells and resident immune cells leading to the recruitment and activation of a host of various inflammatory cell types (Figure 1.2). In similar fashion to an infection, the recruitment of cells into the lung in response to cigarette smoke is due to pro-inflammatory mediators that are produced locally (Janeway et al., 2001). The process is further facilitated by the increased permeability of the endothelium, allowing the leakage of plasma proteins, complement and clotting factors into the tissue and consequently leads to increased adhesion molecule expression on the endothelial cells. This facilitates the recruitment of leukocytes to the site of injury or infection.