The growing prevalence of chronic respiratory diseases (CRDs) has increased morbidity and mortality rates worldwide [1]. Chronic respiratory diseases include chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, pneumonia, lung cancer, chronic bronchitis, pulmonary sarcoidosis and tuberculosis [2]. COPD causes 81.7% of CRD deaths and is the third-leading cause of death worldwide, killing almost 3.2 million people annually. Meanwhile, pneumonia is the leading cause of death among geriatric (>65 years old, elderly) and paediatric (<5 years old, children) patients [3]. The World Health Organization (WHO) reported that around 6.8 million people’s lives abruptly ended mainly due to respiratory illnesses during the COVID-19 pandemic era [4]. Thus, the management of CRDs was given priority, encompassing the invention of new drugs, vaccines, antibiotics, cortisone, ventilation tools, inhalation therapies and advanced lung surgical intervention [5]. However, developing drug-resistant organism strains and variants make available treatments less effective [6,7]. Hence, more efficient and atoxic drugs are preferable to ease CRD management, especially during the pandemic. Scientific interest is supported by the fact that more than thirty per cent of FDA-approved drugs are of natural origin [8]. Historically, natural-based therapies have long been incorporated into CRD treatment. More than 2000 years ago, drug delivery for respiratory diseases was performed via inhalation therapies in ayurvedic medicine [9]. Scientifically, Oriola et al. reviewed the potential of plant-derived natural chemicals, thus supporting their benefits for common respiratory disease treatment [10].

The olive has been one of the most researched plant varieties throughout the decades for its enormous health benefits [11,12]. It is a traditional symbol of Mediterranean culture. This is reflected by a quote from a famous French writer, Georges Duhamel, “There, where the olive tree gives up, is where the Mediterranean ends. The tree of light is the nature and culture of the Mediterranean” [13,14]. The olive fruit and olive oil are the largest products that are commercialised from the olive tree [14], which serve as primary sources of fat in the MedDiet [15]. In 2013, the United Nations Educational, Scientific and Cultural Organization (UNESCO) added the MedDiet to the “Representative List of the Intangible Cultural Heritage of Humanity”. The MedDiet was also specified as being a healthy diet in the 2015–2020 Dietary Guidelines for Americans [16]. Its nutritional values have been correlated with anti-inflammatory [17,18], cardio-protective [19,20,21], anticancer [22,23], anti-ageing [24,25] and neuroprotection [26,27,28] effects. Interestingly, a meta-analysis of cross-sectional studies demonstrated that the MedDiet was associated with longer telomere length and positive ageing [29].

Respiratory infections occur due to bacteria or invading viruses. Antibiotic treatments tend to fail when dealing with antibiotic-resistant bacteria. Respiratory pathogens were reported to exacerbate chronic obstructive pulmonary disease [154]. A meta-analysis of 3338 COVID-19 patients reported that 6.9% of patients were coinfected with bacterial infections [155]. Seven compounds from olive (caffeic acid, verbascoside, oleuropein, luteolin 7-O-glucoside, rutin, apigenin 7-O-glucoside and luteolin 4’-O-glucoside) were found to have an antibacterial effect towards strains such as Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae and antifungal strains such as Candida albicans [156]. Olive secoiridoides also inhibited five different bacterial strains (Haemophilus influenzae, Moraxella catarrhalis, Salmonella typhi, Vibrio parahaemolyticus and Staphylococcus aureus) that commonly cause intestinal and respiratory tract infections [157]. Moreover, aliphatic aldehydes from olives showed similar antibacterial activity [158,159] where alpha- and beta-unsaturated aldehydes were found to have broad-spectrum antibacterial activity, while saturated aldehydes did not show a significant antibacterial effect. Olive extract was reported as being one of the most potent antimycobacterial agents among 63 Mexican traditional medicines postulated as a potential drug for tuberculosis [160,161].

Viral infection is the major reason for respiratory diseases such as pneumonia, bronchitis and COVID-19. The most common viruses that invade the human respiratory system are human coronavirus, rhinovirus (RV), influenza, adenovirus, respiratory syncytial virus (RSV) and so on [162]. Olive compounds have been well reviewed and preferred as a functional food containing antiviral and immune-boosting effects [163]. Additionally, Hydroxytyrosol has been found to disrupt the viral envelope of influenza A viruses, including H1N1, H3N2, H5N1 and H9N2 [164]. Oleuropein has also been reported to inhibit the herpes simplex virus (HSV-1) via phosphorylating PKR, c-FOS and c-JUN in Hela cells [163]. Furthermore, purified HT from olive and a patented HT, HIDROX^®, have been shown to inactivate SARS-CoV-2. They altered the spike protein, significantly impacting the viral genome [165]. A similar effect has been reported in molecular docking by Geromichalou et al. He demonstrated the EVOO compound’s potential to bind to inhibit the SARS-CoV-2 spike protein via targeting angiotensin-converting enzyme 2 (ACE2) and the receptor-binding domain (RBD) [166]. On the other hand, Nrf2 has also been revealed to have the ability to inhibit virus penetration by secreting anti-proteases in COVID-19 patients [167]. Nrf2 activates interferon gene expression to initiate antiviral activity [168]. The research collectively reported findings of olive-derived phytochemicals’ ability to activate the Nrf2 pathway [129,141,142]. Thus, they certainly could play a role in drug design for COVID-19 treatment.

Lung cancer is a leading cause of cancer death to date, which is due to the over-proliferation of respiratory cells [169]. Olive compounds, especially polyphenols, have been well studied for their anticancer effects [44,170,171]. A systematic search and meta-analysis of 45 studies [22] discovered that olive oil consumption prevents cancer. An olive extract and bromelain combination suppressed Benzo[a]pyrene (BaP)-induced lung carcinogenesis by decreasing the expression of inflammation and oxidative markers (Nrf2, NF-κB) [142]. In another study, oleic acid, and its metabolite oleoyl ethanolamide, induced apoptosis in lung carcinoma cell lines by decreasing programmed death-ligand 1 (PD-L1), the tumorigenesis marker and the phosphorylate STAT pathway [172]. An extract from olive mill wastewater (OMWW A009) limited lung cancer cell propagation by activating apoptosis. The extract was able to reduce CXCL12 and CXCR4 chemokines and STAT3 phosphorylation [173]. Besides, (-)-Oleocanthal (OC) disrupted metastasis by inhibiting the activation of mesenchymal-epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) in adenocarcinoma cells A549 and NCI-H322M [174]. The same study showed that eight weeks of OC supplementation prevented brain and other organ metastasis in mice models. The c-MET inhibitors showed promising results in lung cancer prevention in both animal models and clinical trials [175,176]. Hydroxytyrosol was also reported to have reversed TGFβ1-induced EMT in respiratory epithelial cells by inhibiting AKT and SMAD2/3 expression [177]. Thus, hydroxytyrosol could be exploited for cancer prevention by targeting c-MET inhibition.