Book ReviewTargeting eosinophils in chronic respiratory diseases using nanotechnology-based drug delivery
Introduction
Chronic respiratory diseases (CRDs) are affect the lungs and other parts of the respiratory system. Some of the lethal CRDs are Asthma, Chronic Obstructive Pulmonary Disease (COPD), COVID-19, Eosinophilic granulomatosis with polyangiitis (EGPA), Lung Cancer, and Pneumonia [1,2]. Some of these CRDs are claimed to be irreparable, which means they cannot regain normal functioning; therefore, they are stated as fatal diseases. According to World Health Organization (WHO), 334 million people have asthma, and 65 million have COPD, out of which 3 million die yearly. Concerning the current pandemic situation, WHO has stated that approximately 1 million people out of 28.9 million are prone to COVID-19, and this number is increasing exponentially [[3], [4], [5]].
Moreover, lung cancer often expressed as the lethal killer, has been responsible for 1.6 million deaths worldwide [[6], [7], [8]]. Apart from these fatal diseases, a few other respiratory diseases like Eosinophilic granulomatosis with polyangiitis (EGPA), Loffler's syndrome, and Pneumonia [5] also showed an elevated level of eosinophils in both the blood and the lungs. This makes eosinophil the viable target because it is an immune-mediator, performing diverse functions with inflammatory cells like maintaining homeostasis and indicating disease conditions in different tissues and cells of the body [9]. Additionally, elevated eosinophil count in the lungs causes the secretion of various chemokines, cytokines, proteins, and growth factors, leading to unceasing inflammation. Sometimes, it leads to permanent damage to lung tissues [10,11].
The first line of treatment for CRDs has always been traditional pharmacotherapy, which involves prescribed doses of several medicines, primarily antibiotics, anti-inflammatory, bronchodilators, and corticosteroids [12,13]. But these conventional approaches are not effective in curing these CRDs solely. For example, the therapies used to treat asthma, COPD, and other respiratory diseases primarily focus on treating the symptoms and reducing the chances of exacerbations. The foremost reasons for the onset of CRDs include exposure to allergens, chemical dust, fume, and cigarette smoke. Although available pharmacotherapy suppresses immunological symptoms, it is frequently ineffective in treating these multifactorial CRDs such as EGPA, pneumonia, and lung cancer [14]. Even though pharmacotherapy approaches play an important role in treating and managing patients throughout their lives, their limitations have encouraged us to discover novel therapeutic options. Recent advancements in nanotechnology have revealed the significance of nano-drug delivery systems, which have shown promising results in pharmacotherapy [15,16].
Additionally, these nanocarriers can target the desired site, significantly improving the therapeutic drug's pharmacokinetics. Eosinophils are now the most effective target for the treatment of CRDs. In the line of interest, targeting eosinophils via nanocarriers drug delivery systems can unlock the unseen potentials of therapeutic importance [17,18]. Hence, this review aims to provide insight into the role of eosinophils in the treatment of CRDs with the help of the nanocarrier drug delivery system.
Chronic Respiratory Diseases (CRDs) have become the most prominent health hazard among all the socioeconomic classes and a significant factor in morbidity and mortality worldwide [19,20]. Therefore, global assessment of CRD patients, the World Health Organization (WHO) introduced the Global Alliance against Respiratory Diseases (GARD) in 2016. The role of GARD is to provide a comprehensive report of CRD patients' burden among 195 countries/territories. Moreover, about 7.63 million (66.7%) people have died of these CRDs due to tobacco consumption, in/outdoor pollution, allergens, diet, physical inactivity, obesity, and occupational and environmental exposures [21,22]. Some of the common CRDs with associated complications are depicted in Fig. 1.
Asthma is a long-lasting, inflammatory disease of the upper airways which usually occurs in the early stage of life. In this disease, the airways get inflamed, narrowed, thickened, and filled with mucus, restricting airflow [23]. This is the reason for wheezing sounds produced while coughing. The asthma symptoms include tightness in the chest, shortness of breath, coughing, fatigue, wheezing, and conjunctivitis. In 2020, nearly 3.39 million asthma cases globally and about 4.1 million deaths had been recorded for asthma [24]. Moreover, more than 80% of asthma-related mortality has been reported in middle/low-income countries. The prevalence of asthma is usually high in nations like Great Britain, Australia, Canada, Peru, Brazil, and the United States, whereas China, Russia, and India have a low prevalence rate [25].
Even though most respiratory disorders share similarities, asthma has unique clinical features that distinguish it from COPD and other pulmonary diseases [26,27]. The pathogenesis of asthma includes hyper-responsiveness of the non-ciliated epithelium in the upper airways, including bronchi, bronchioles, and trachea. This hyper-response of airway epithelial is generally triggered by allergens (pollens, dust particles) or environmental stimuli. This hyperresponsiveness leads to airway remodeling of smooth muscles and goblet cells, which causes constriction, inflammation in the bronchioles, and hyper-secretion of mucus [[28], [29], [30]]. Eosinophils play a crucial role in hyperresponsive reactions and are often associated with significant complications [31].
COPD, commonly referred to as Chronic Obstructive Pulmonary Disease, is a progressive pulmonary condition involving chronic bronchitis and emphysema [7]. During the early stages of COPD, emphysema gradually deteriorates the air-sacs of the lungs, obstructing the airflow. In contrast, bronchitis causes narrowing and thickening of bronchioles and is also responsible for producing mucus plugs [32,33]. Globally, around 65 million people have suffered from COPD, and about 3.19 million people die annually [34,35]. COPD mortality/morbidity rates were significantly higher in 2015 than in 2010, corresponding to 2.8–3.0 million people. Hence, it is proclaimed the 3rd leading cause of death globally. COPD is expected to be the leading cause of high mortality and morbidity rates in the next 15 years [36]. Countries such as Austria, Canada, Australia, Brazil, South Africa, Italy, Uganda, and the U.S.A have recorded a high number of COPD patients compared to countries like Peru, Abu Dhabi, India, Singapore, Thailand, etc. [37].
COPD is mainly caused by cigarette/tobacco smoking, toxic particulates, and chemical irritants in the polluted air [38]. It is also caused due to some genetic factors like deficiency of α-1-antitrypsin, which leads to lung deterioration [39]. COPD pathological effect is also observed in bronchioles at the terminal end, as augmentation in air spaces wrecks the alveolar wall of bronchioles. Further, activation of eosinophils, structural amendment, and inflammation in small airways also enhance the severity of the disease [40]. Symptoms of COPD include cough with or without mucus, weight loss, wheezing sound, chest tightness, and flu [41].
COVID-19 is a viral infectious disease caused by a new strain of coronavirus that was not previously discovered in humans and named “novel-Coronavirus (nCOV-19)”. Coronavirus is species of virus that is associated with different pulmonary diseases, such as common cold, Severe Acute Respiratory Syndrome (SARS-CoV), and Middle East Respiratory Syndrome (MERS-CoV) [42]. Till November 24, 2020, around 59.1 million people had been infected by a coronavirus, and about 1.4 million people had died globally. Worldwide, the most COVID-19 cases are reported in the U.S.A., India, Brazil, Russia, and France, contributing approximately 60% of the total cases [43].
COVID-19 is a zoonotic virus spreading among different animals and humans. Detailed studies showed that SARS-CoV was transferred from civet cats, and MERS-CoV was transferred from dromedary camels to humans. Similarly, in the case of nCOV-19, there is a high level of genomic similarity with the bat-coronavirus. However, there is no evidence yet, confirming that it has emerged from a bat-borne virus [44]. The pathogenesis of this disease includes bilateral pneumonia and pleural effusion. Bilateral pneumonia causes the inflammation of alveoli which later get filled with pus.
In contrast, pleural effusion leads to fluid accumulation in the pleural cavity, restricting lung expansion. The common symptoms of COVID-19 include breathlessness, fever, dry cough/cough with mucus, and loss of taste and smell sensation. In severe cases, the persistent viral infection causes the onset of other ailments like influenza, Acute Respiratory Distress Syndrome (ARDS), and organ failure, which often leads to death [[45], [46], [47]].
Eosinophilic Granulomatosis with Polyangiitis (EGPA), also known as Churg-Strauss Syndrome, is a rare auto-immune pulmonary disease that primarily affects the upper airways. The estimated prevalence of EGPA is around 10–14 million people globally, corresponding to 2.5 cases over 10,00,00 people every year. The high majority of EGPA is recorded in Australia, Canada, Brazil, United States, and low in Asian (India and China) and Europe (Russia) countries [48,49]. It involves three stages, viz. allergic, eosinophilic, and vasculitis [50,51]. The allergic stage is characterized by an allergy/asthma or rhinitis, followed by the eosinophilic stage, distinguished by high eosinophil levels that last for months or a year. At this stage, the hyper-eosinophilic condition affects the lungs and the digestive tract, causing night sweating, weight loss, asthma, abdominal pain, cough, fever, malaise, gastro-intestinal bleeding, etc. Vasculitis is the final stage and a defining feature of this chronic disease. It usually occurs after hyper-eosinophilia. During systemic small-vessel vasculitis disease, arterioles/venules are inflamed (thickened, narrowed), restricting blood flow to tissues and body organs [[52], [53], [54]]. The pathogenesis of this disease is multifactorial, as it can be triggered by medication, allergens, or genetic factors, particularly HLA-DRB4, which has been identified as a genetic risk factor involved in complex pathophysiology. The clinical signs of EGPA include chest pain, shortness of breath, skin lesions, sinusitis, blood in stools, and muscle/joint pain [55,56].
Lung cancer is a severe pulmonary disorder characterized by genetic material (DNA) alteration. This disruption of cell growth and proliferation system eventually leads to cell mass formation, termed a tumor. Tumors are classified as “benign” or “malignant” based on their ability to spread, i.e., metastasis [24,57]. In 2020, about 2.29 million cases (1.25 million females and 1.16 million males, respectively) and 1.35 million deaths (63,220 females and 72,500 males, respectively) had been recorded for lung cancer [58,59]. Therefore, lung cancer is the most common cancer in men and women, accounting for 25% of cancer-related deaths worldwide. The nations like Greece, Belgium, Denmark, Guam, Serbia, Hungary, Turkey, India, and Montenegro have been accorded the increasing trend of lung cancer [60].
Contributing factors in lung cancer include cigarette smoking, asbestos exposure, radon, biomass fuel, passive inhalation of cigarette smoke, etc. [61,62]. Lung cancer can develop in any part of the lungs; however, 90–95% of lung cancer develops in the airway epithelial cells. Symptoms of lung cancer include lack of appetite, fatigue, respiratory illness, coughing, clubbing of fingers, recurrent chest inflammation, thrombocytosis, and weight loss [63].
Pneumonia is an infectious lung disease that causes the inflammation of air sacs within one or both lungs. In this disease, the air-sacs become clogged with purulent fluid or pus, which decreases the surface area for gaseous exchange [64]. Pneumonia is caused by different bacterial species like Mycoplasma pneumoniae, Haemophilus influenzae, Staphylococcus aureus, etc. [65]. However, various fungi such as Aspergillus spp., Coccidioides immitis, Coccidioides posadasii, and some viral moieties act as causative organisms [66,67]. Pneumonia is the most common pulmonary disorder globally, affecting approximately 450 million people yearly. In 2017, about 2.56 million people died as a result of pneumonia all over the world [68]. Out of which, more than 0.8 million deaths were of children (under the age of 5 years). Household air pollution was responsible for 45% of these children's deaths [69]. The most frequent death cases have been reported in Southeast Asia and Sub-Saharan Africa, including India, Afghanistan, Democratic Republic of Congo, Ethiopia, Indonesia, Pakistan, Philippines, and Nigeria, due to the poor hygienic conditions, malnutrition, and air pollution. In contrast, fewer pneumonia deaths have been reported in North Korea, China, Peru, and Mexico [70]. The pathogenesis of pneumonia patients involves the inflammation in the lining of the pulmonary pleura resulting in extreme pain while coughing and breathing [71,72]. Pneumonia involves chest pain, shortness of breath, sputum in cough, fever, diarrhea, and fatigue [73,74].
Eosinophils are a vital immune-mediator that performs various cellular functions and plays an essential role in disease pathology and homeostasis across multiple body tissues [75]. These are generally derived from the pro-genitor stem cells found in the bone marrow, which enter the bloodstream during maturation. In the blood circulation, IL-3 and IL-5 are the central cytokines that promote eosinophils' rolling, adhesion, trafficking, and survival. Under healthy conditions, eosinophil count and activity are low in the blood. However, during the disease conditions, eosinophils become highly active in response to pro-inflammatory mediators like IL-3, IL-5, and GM-CSF and start migrating towards the site of inflammation [76,77]. After reaching the targeted site, eosinophils trigger different eosinophil-mediated inflammatory responses. Certain chemotactic factors, such as CCL-5, CCL-7, CCL-11, CCL-13, CCL-15, CCL-24, and CCL-26, regulate eosinophil migration towards the site of inflammation in the lungs. These chemotactic factors act on the CCR-3, CRTH-2 receptors (expressed on T-helper-2 (Th2) cells), and its ligand prostaglandin D-2 (PGD2) [78,79]. Various pro-inflammatory mediators, such as basic proteins (eosinophil-cationic protein, eosinophil-derived neurotoxin, and eosinophil-peroxidase), chemokines (CCL-5, CCL-7, CCL-26), cytokines (IL-3, IL-5, IL-10, IL-13, IL-25), and specific growth factors like Transforming Growth Factor (TGFα & β), Tumor Necrosis Factor (TNF); are also released by the eosinophils which play a significant role in various cell signaling pathways associated with different pulmonary diseases [80]. Although eosinophils play an immune-modulatory role, they are recruited inside the airway epithelium by the influence of other immune-mediator cells (ILC-2, basophils), resulting in necrosis and sustained inflammation within the lungs, as depicted in Fig. 2.
Various studies have revealed that hyperactivation of eosinophils permanently damages the lung. Therefore, determining eosinophils may serve as a practical element for determining the onset of CRDs. Eosinophils count can be determined through blood, sputum, or Broncho-alveolar lavage (BAL) fluid, either as a percentage of total leukocytes or as an absolute concentration (cell/μl). The quantification of eosinophils can also be done via a lung tissue biopsy. Moreover, eosinophils concentration only provides information about the overall eosinophil levels but does not provide any information regarding its activation [81,82]. Furthermore, eosinophil concentration in blood is a good predictor of its concentration in the airways compared to the concentration of sputum/bronchial sub-mucosal samples. Because the blood-eosinophil count is simple, inconsistent, and samples are easily obtained, it is preferred over other clinical methods [83]. However, it may be noted that the blood eosinophil count is only a surrogate biomarker for airway eosinophilia in COPD and the eosinophilia of the sputum is seen in only a third of stabilized COPD patients, if not the exacerbated ones. Negewo et al. reported a statistically significant correlation between the eosinophil count in the peripheral blood and sputum samples [84].
In recent studies, a wide range of blood samples from CRD patients were found to have a high eosinophil count. For instance, a study of 491 asthmatic patients found that patients with a high eosinophilic count, i.e., ≥300 cells/μl, have significantly higher mean eosinophil concentration in induced sputa than patients with mean blood eosinophils count <300 cells/μl [85]. A recent study on COPD patients reported the high eosinophil concentration, i.e.,≥250 cells/μl, in BAL fluid, bronchial mucosa, and sputum in contrast to low eosinophil concentrations, i.e., <150 cells/μL in blood [82,86]. Similarly, high eosinophil concentrations are recorded in patients suffering from COVID-19, EGPA, lung cancer, and Pneumonia.
Section snippets
Synergism between eosinophils and cell signaling pathway involved in chronic respiratory diseases
Eosinophils are granulocytic white blood cells with distinct phenotypical characteristics such as bi-lobed nuclei and acidic cytoplasmic granules. The pathogenesis of eosinophils mainly occurs inside the tissues and is associated with different mechanisms involving eosinophilic recruitment, as illustrated in Fig. 3. Eosinophils are synthesized from pluripotent CD-34 stem cells in the bone marrow [76]. Eosinophils differentiate in response to the stimuli Granulocyte Monocyte Colony Stimulating
Current treatments available for treating chronic respiratory diseases
Although CRDs are incurable, different chemotherapeutic agents are used to curb the clinical symptoms, reduce mortality/morbidity, and improve the quality of life. Presently, progressive advancement has been made to improve drug efficacy and drug delivery. However, effective management of CRDs remains a challenge [129]. The current treatment involving different therapeutic regimens for CRDs have been discussed below:
Challenges associated with conventional treatment of chronic respiratory diseases
These CRDs have complex pathophysiology, and severe clinical symptoms managed using traditional methods such as long-term antibiotics, bronchodilators, or anti-inflammatory drugs. Furthermore, the continued use of these conventional medications creates additional challenges that have already been discussed [160]. Antibiotics are the primary remedies that are used to treat respiratory infections. But continuous use of these drugs, especially macrolides, cause impairment in phagocytosis and
Advantages of novel drug delivery system
There is a need to explore a novel and improved drug delivery approach to circumvent the limitations associated with the conventional therapeutic approach. The new approach should increase the residence time of the drug and can be quickly cleared from the body [167,168]. In light of the abovementioned requirements, a novel drug delivery system based on nanoparticles has emerged as an effective approach for treating various CRDs [169]. Nanoparticles Drug Delivery System (NDDS) has an advantage
Conclusion
Eosinophils are an essential immune mediator that performs various cellular functions and plays a vital role in disease pathology and homeostasis across multiple body tissues. It also plays a role in regulating the functional homeostasis of various non-immunocompetent tissues. A complex eosinophil-containing cell signaling pathway involves B cells, Th-2 lymphocytes, mast cells, and circulating platelets activated by inflammatory stimuli at the inflammation site to protect the host from various
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work is supported by Lovely Professional University, India from undergraduate students capstone projects grants (Sharma P and Satija S). This work is completed with the help of Sohal S.S of University of Tasmania, Australia who is supported by the grants from Clifford Craig Foundation Launceston General Hospital, Rebecca L. Cooper Medical Research Foundation, Lung Foundation Australia, and LAM Australia Research Alliance.
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