Inflammatory and Immunological Profile of Chronic Obstructive Pulmonary Disease. Basic Research and Clinical Application

Respiratory diseases are among the leading causes of morbidity and mortality in the world population. Our understanding of the molecular mechanisms leading to recognition of infectious pathogens and harmful endogenous signals by the innate immune system and the adaptive immune system has improved significantly in recent decades. There is increased evidence of the key role of the immune system with its pattern recognition receptors (PRRs) in infectious and non-infectious lung diseases. The PRRs are a family of sensors able to sense different microbial molecules as well as endogenous molecules which are released by the host tissue damage. The commitment of PRRs is a prerequisite for the initiation of immune and inflammatory response to infection and tissue injury that may beneficial or harmful. The PRRs are germline encoded, evolutionarily conserved molecules and consist of Toll-like receptors, NOD-like receptors, RIG-I-like receptors, C-type lectin-like receptors and cytosolic DNA sensors. This chapter summarizes the prominent role of transmembrane and cytosolic PRRs in the pathogenesis of obstructive lung diseases (COPD and bronchial asthma). The PRRs and their signals represent promising targets for prophylactic and therapeutic strategies in various lung diseases.

Chronic obstructive pulmonary disease (COPD) is a global public health problem. It has an overwhelming prevalence, yet accepted therapies are ineffective in reducing disease progression. Bronchodilators, the mainstay of COPD treatment, only provide symptomatic relief. Therefore, to provide a superior approach, it is important to better understand the rationale behind therapy and the underlying mechanisms by which the inflammatory process, through various pathogenic pathways, leads to deterioration. Cigarette smoke and other pollutants/biomass fuels affect the lung ability to counterbalance proteases and neutralize different types of stress. Even if the initial noxa is discontinued, inflammation, infection and autoimmunity promote a chronic lung inflammatory response, leading to the development of emphysema and small airway disease. This is due to continuous endogenous production of reactive oxygen species, nitrative, carbonyl, inflammatory and endoplasmic reticulum stress. The process then continues into a harmful spiral and systemic disease. The objective of this paper is to offer an updated review of COPD, simplifying the integration of basic science research and introducing the concepts and evidence of therapeutic alternatives. Probably there is no unique effective therapy, but several combinations of drugs might be required to impact the different subcellular compartments and obtain a more effective therapy in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. While other diseases associated with smoking have entered a plateau with respect to mortality, mortality associated with COPD has been increasing. Several facts seem to explain this phenomenon such as the increase in smoking habits in developing countries, the increase in life expectancy in high-income countries, and the growing increase in COPD not associated with smoking. A very striking finding of the entity is that the deterioration in lung function and therefore in mortality, is not stopped by the fact of suspending exposure to the environmental noxa. This could also contribute to this increase in mortality. The explanations considered are two: frequent respiratory infections in these patients, which are the leading cause of exacerbations, generate endogenous oxidative stress due to mitochondrial respiration, which perpetuates the inflammatory process, although exogenous exposure is suspended. The other explanation is autoimmunity playing a pathogenic role in the development and evolution of COPD. This chapter, therefore, aims to review the evidence of the immunological phenomenon in COPD giving special emphasis to two aspects: autoimmunity generating COPD and the possible therapeutic avenues that can be derived from this perspective. This last aspect seems crucial, especially since the current treatment does not prevent the deterioration of lung function or reduce mortality. Mitochondrial dysfunction in COPD and its therapeutic implications are also discussed. At the end, some suggestions are made about future research.

Muco-obstructive lung diseases, including chronic obstructive pulmonary disease, asthma, cystic fibrosis, non-cystic bronchiectasis, and primary ciliary dyskinesia, are characterized by intrapulmonary accumulations of hyper-concentrated mucus. Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with muco-obstructive diseases. Ultimately, the mucus accumulation in diseases reflects the failure of said clearance mechanism. Given the multifunctionality of mucus, the various mechanisms of mucus production and exposure to the environment, but also to the systemic circulation, it is not surprising that both its genesis and its operation can be compromised in said pathologies. We proceed to review the biochemical and biophysical properties of mucus relative to airway function, the mucin concentration in health and diseases and the integrated cilia and cough-dependent mucus clearance. Then we proceed to review various diseases that have mucus dysfunction in common, the mechanism that generates this dysfunction and how it impacts the symptoms and the natural evolution of these pathologies. At the end it is discussed how restoration of cough efficacy may be most effectively provided by restoring mucus concentrations to normal ranges with hydrating agents coupled with viscosity-lowering agents.

In COPD, tobacco smoking is established as a major risk factor. However, especially in the last 15 years, there are studies have shown that long-term exposure to biomass fuel smoke to cook and heat homes, also carries a high risk for the development of COPD. This occurs particularly in developing countries, and women and children have the highest exposure rates and are therefore more likely to develop the disease. It is estimated that 25-45% of patients with COPD have never smoked, and the burden of COPD not associated with smoking is possibly higher than previously believed. Although exposure to biomass is the major risk factor for COPD not associated with smoking, there are other associated factors such as occupational exposure to dust and gases, HIV/AIDS, lower respiratory tract infection (particularly in the childhood), chronic asthma, external pollution, and poverty. This chapter exposes the evidence of this association, and some clinical, functional, anatomopathological and therapeutic aspects and particularly the need for preventive interventions to face this other side of the entity that seems to be increasing.

Although exposure to biomass is the major risk factor for COPD not associated with smoking, there are other associated factors such as history of pulmonary tuberculosis (PTB). PTB affects more than 9 million people and kills 1.5 million people each year. Prevalence of airflow obstruction varies from 28% to 68% of patients with PTB and the association occurs mainly with the COPD phenotype. Such infection is associated with airway fibrosis, and the immune response to mycobacteria can result in airway inflammation, which is characteristic of COPD. The degree of airflow obstruction is correlated with the extent of the disease. This review exposes the evidence of this association (TOPD), and some clinical, functional, anatomopathological and therapeutic aspects. At the end of the chapter, the interrelationship between PTB and COVID-19 is concisely explored.

Few diseases have a greater effect on the health of young children than viral respiratory illness of lower tract. This does not happen in adults, possibly due to the different states of activation and expression of the innate immune response and acquired immune responses in these two age groups. Bronchiolitis is a general term used to describe non-specific inflammatory injury that primarily affects the small airways and generally limits the extent to interstice. In the adult clinic, conventional and high-resolution radiology and respiratory functional studies are suggestive of the diagnosis but the etiology usually requires tissue. For this reason, in this chapter, although there are clinical and radiological classifications, we will use the histologic classification. The goal is a simple, concise, and updated monograph issue discussing the different types of adult bronchiolitis, pathophysiology, diagnosis, and current therapeutic options. A short discussion on SARS-CoV-2 bronchiolitis is also included at the end.

Inhaled bronchodilators with or without inhaled steroids (IGCs) are the mainstay of pharmacological treatment for stable obstructive airway diseases, including beta 2-agonists and muscarinic antagonists. Long-acting muscarinic antagonist bronchodilators (LAMA) and long-acting \(\beta\)2-agonists (LABA) are the treatment of choice for moderate to severe chronic obstructive pulmonary disease (COPD). Also, some studies have demonstrated the benefit of LAMA in the treatment of difficult-to control asthma and the potential use in asthma-COPD overlap (ACO). Control of airway tone in health and disease states, cholinergic and adrenergic receptors, signaling, molecular biology of mediators, and airway muscle contraction / relaxation mechanisms are reviewed concisely and as they may be handled pharmacologically. Subsequently, the evidence of the role of the LABA / LAMA combination in the entities, their complementary mechanisms of action and other alternative mechanisms of action as well as potential deleterious effects is discussed.

Glucocorticoids are the most effective anti-inflammatory drugs for asthma and some groups of COPD patients. Glucocorticoids suppress inflammation by several mechanisms. Its principal action at therapeutic doses is due to trans-repression of activated inflammatory genes, by the recruitment of the enzyme histone desacetylase-2 and the subsequent remodeling of chromatin. At higher concentration, glucocorticoids act as trans-activators, acetylating histones and stimulating the transcription of anti-inflammatory genes. Eventually, this mechanism could be involved in the activation of genes related to side effects. Post-transcriptional effects that modulate the stability of mRNA have been proved. This mechanism of action is known as genomic. In the last decades, a mechanism of local action with the use of glucocorticoids involving an interaction between glucocorticoids and noradrenaline has been described, through a membrane receptor in the smooth muscle of the blood vessels that reduces hyper-perfusion and mucosal edema. This mechanism is known as non-genomic. This chapter discusses and compares both mechanisms by establishing similarities and differences between the two.

Molecular oxygen is vital for energy which is essential for life. The fact that we all need oxygen to live might make us think that the use of supplemental oxygen in every hypoxemic patient seems obvious. This is a fallacy. The survival of all metazoan organisms is dependent on the regulation of the delivery and use of oxygen to maintain a balance between the generation of energy and the production of oxygen radicals, potentially toxic. HIF (hypoxia inducible factor) is a transcription factor or nuclear messenger that should be conceptualized as a master regulator of oxygen homeostasis. Therefore, it is proceeded to discuss how its action in hypoxia conditions the activation of diverse genes that codify the synthesis of proteins that explain some of the clinical manifestations and the events of hypoxia. We also discuss how inflammatory diseases of the respiratory system can perpetuate, in the presence of oxygen at inappropriately high doses, the oxidative stress that in turn amplifies the inflammatory phenomenon. Subsequently, the doses of ambulatory oxygen are defined in conventional indications and in some unconventional indications such as air travel and high altitude. Finally, some research avenues are mentioned in this topic.

Bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) are two major health problems whose incidence is increasing. Both are recognized as major causes of morbidity and mortality worldwide. Never as now is better known the pathophysiology of both, as well as their inflammatory, cellular, and immunological profiles. It has powerful diagnostic, image, gasometric, functional, cellular, and immunological tools, as well as abundant basic, clinical, genetic, and therapeutic research. However, despite having international guidelines based on evidence, the responses to the treatments are sub-optimal in both. The definition of asthma states that it is inflammatory event.  In BA the incidence of uncontrolled patients is high and in COPD, treatment with inhaled bronchodilators and glucocorticoids (IGCs) improves symptoms and quality of life but does not impact the deterioration in lung function or improve life expectancy. The problem is amplified by patients in which the two entities overlap, and this creates problems of diagnosis and treatment. Therefore, the research of new therapeutic tools (such as antioxidants, biological and those that impact the function of mitochondria) is vigorous. This chapter therefore aims to establish, as clearly as possible, the differences and similarities between BA and COPD to give the clinician a tool that brings him closer to a more precise diagnosis and a more rational treatment.

With the pandemic, as countries went into lockdown and industrial activities shut down, pollutant emission reduced substantially, and environmental air quality improve. This could have contributed to the reported of reduction in hospital admission for COPD during the COVID-19 pandemic, but COPD patients as at high risk of developing severe COVID-19 and multimorbid survivors frequently have required prolonged ICU stay. People with asthma do not appear to be at increased risk of acquiring COVID-19, and systematic reviews have not shown an increased risk of severe COVID-19 in people with asthma. Overall, people with asthma are not at increased risk of COVID-19-related death. Patients with COPD presenting with new or worsening respiratory symptoms, fever and or any other symptoms that could be COVID-19 related, even if these are mild, should be tested for possible infection with SARS-CoV-2. Spirometry should be restricted to patients requiring urgent or essential tests for the diagnosis of COPD, or to assess lung function status for interventional procedures or surgery. Patients should keep tasking their respiratory medications for COPD without changes. Shielding/sheltering or physical distance are not same of social isolation and inactivity. They should ensure they have enough medication and contact with friends and families by telecommunications.