Cells that are associated with innate immunity in the lung include macrophages, dendritic cells, monocytes, and neutrophils [15]. The recognition of microbes is first done by PRRs expressed in alveolar macrophages, dendritic cells, and epithelial cells. TLRs are a major family of PRRs, and humans have ten kinds of TLRs to recognize pathogens. The TLRs associated with COPD are TLR6 and TLR9 [16, 17]. They usually recognize bacteria or viruses, but cigarette smoke can also induce pulmonary inflammation via TLRs [17–19]. Additionally, the interaction between TLRs and EGFR increases IL-8 and vascular endothelial growth factor (VEGF) [20]. Through TLR stimulation, reactive oxygen species (ROS) activate the latent form of TNF-α-converting enzyme (TACE), which cleaves the transforming growth factor (TGF)-α proligand that activates EGFR. This results in signaling that leads to IL-8 and VEGF production [21, 22]. Indeed, it was reported that cigarette smoke augments TLR3, which stimulates IL-8 release and increases total MMP9 activity in the airways [19]. IL-8 leads to the recruitment and activation of neutrophils in the airways (see Sect. 4.3.2.2).

NLRs represent a group of key sensors of infections and tissue damage in the lung [23]. Activation of most known NLRs leads to the production and release of proinflammatory cytokines and induction of cell death [23]. Ligand recognition by NOD1 and NOD2 receptors leads to signal transduction through receptor-interacting protein 2 (RIP2) kinase, with downstream activation of MAPKs and transcription factor nuclear factor-kappa B (NF-kB). This then leads to the activation of genes encoding different cytokines and chemokines such as IL-8 [23]. Inflammasomes consisting of one or two NLR proteins serve as platforms for autocatalytic caspase-1 activation, which in turn critically regulates IL-1β and IL-18 production, inducing an inflammatory form of cell death called pyroptosis. Importantly, the NLR protein 3 (NLRP3) inflammasome responds to a vast range of sterile stimuli particularly DAMPs released by dying cells such as adenosine triphosphate (ATP), uric acid metabolites, and biglycan as well as hyaluronan [23]. Experimental studies in mice suggest that activation of NLRPs by some of those DAMPs might have important functions in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), COPD/emphysema, and lung fibrosis [23].

Unlike other PRRs, there are almost no reports about the relationship between the components in cigarette smoke and RLRs. However, RLRs are indispensable in viral infection, and they are intimately associated with COPD progression after smoking cessation.

RLRs, including RIG-1 and melanoma differentiation-associated gene 5 (MDA-5), are important pattern recognition receptors for viral elimination [14]. When viral RNA binds to the C-terminal regulatory domain of RIG-1 or MDA-5, it can initiate a signaling cascade. This cascade leads to activation and nuclear translocation of the transcription factors NF-kB and interferon regulatory transcription 3 (IRF-3), which are needed to turn on transcription of interferons (IFNs) [14]. Viral infection is a significant cause of COPD and acute exacerbations of COPD [14]. Up to half of COPD exacerbation cases are associated with viral infections [14]. The top four causes are rhinovirus (RV), coronavirus, influenza virus, and respiratory syncytial virus [14]. Recent studies provide evidence that MDA-5 is responsible for recognizing RV and subsequently activating signaling pathways, causing an exaggerated inflammatory response in patients with COPD. These responses include increased levels of IL-8, IL-6, CXC-chemokine ligand 1 (CXCL1), TNF-α, IL-1β, and monocyte chemotactic protein 1 (MCP-1) [14].

RAGE are members of an immunoglobulin superfamily of cell surface receptors that function as pattern recognition receptors capable of signal transduction after interaction with diverse ligands [24]. RAGE is upregulated wherever its ligands accumulate in chronic conditions such as inflammation, cardiovascular disease, diabetes, cancer, and neurodegeneration [25]. RAGE expression increases in the pulmonary epithelium when tobacco smoke is present [24]. RAGE engagement activates an inflammatory signaling pathway. Smoke-induced RAGE expression mediates cytokine secretions via Ras, a GTPase that influences Raf/MAP kinase, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK)/p38, NF-kB [25], and the Rho proinflammatory pathway [24]. At minimum, RAGE signaling orchestrates polymorphonucleocyte recruitment and reservoirs of elastolytic enzymes including MMP9 and other mediators of emphysema regulated by RAGE signaling [24]. Recently, both soluble and circulating forms of RAGE were said to be the useful biomarkers for the presence or progression of emphysema because RAGE is generated via cleavage of full-length RAGE from the cell surface by metalloproteinases such as disintegrin, metalloproteinase domain-containing protein 10 (ADAM10), and MMP9 [25].

Little is known about the role of B cells in the development of COPD [28]. The presence of B cells in lymphoid follicles has been reported in the airways and parenchyma of patients with COPD and of mice exposed to cigarette smoke [29]. In mice, the development of lymphoid follicles was progressive over time and correlated with the increase in airspace enlargement [28]. The B-cell follicles are surrounded by T cells, with the majority being CD4+ [28]. The B cells are interspaced by follicular dendritic cells that are necessary for antigen presentation and affinity maturation [28]. Follicle formation is associated with increased levels of cytokines including IL-4, IL-6, IL-8, and IL-13 [28]. These cytokines are essential for the formation and differentiation of germinal centers [28]. Overexpression of IL-13 in mice results in severe emphysema [28]. The absence of bacterial and viral products in the follicles suggests that oligoclonal B cells arise in response to lung antigens [30]. Nevertheless, viral and bacterial infections could be important in perpetuating the inflammatory process and are regarded as the main cause of the exacerbations in COPD. Barry et al. [28] hypothesized that cigarette smoke-induced breakdown products of the extracellular matrix might also be immunogenic and trigger a specific B-cell reaction [28].

It is likely that antigens from necrotic and apoptotic cells in the lungs of smokers are taken up by dendritic cells and presented as antigens to CD8+ T lymphocytes [29]. Activated T cells leave the blood vessels and enter the lung parenchyma. In the lungs of smokers with COPD, CD8+ and CD4+ T cells express the tissue-specific chemokine receptors CXCR3, CXCR5, and CXCR6 [30]. These receptors correlate with the severity of the disease [29]. In both the airway and alveolar compartments, the CD8+ cytotoxic T cell is the predominant T cell in patients with COPD and causes tissue injury [29]. Any cell that displays MHC class I can be a target of CD8+ cytolytic T cells. After a cytolytic attack, target cells die of apoptosis or necrosis from the damage done by perforin, granulysin, or granzyme A or B (Fig. 4.3), all of which are proteolytic enzymes released by CD8+ T cells [15] in the lungs of patients with COPD.

CD4+ T cells also play an important role in COPD. The cytokine IL-17 is a 17-kDa molecule that is produced in vitro by CD4+ and CD8+ subsets of T lymphocytes from humans and mice [31]. IL-17A signaling appears to be crucial for the formation of cigarette smoking-induced emphysema [16]. The frequencies of Th17 (CD4 + IL-17+) and Tc17 (CD8 + IL-17+) cells in the lungs of smoke-exposed mice and smoke-ceased mice are positively correlated with emphysematous lesions [30].