The Role of Lycopene in Chronic Lung Diseases

Lycopene, a naturally occurring non-provitamin A carotenoid pigment, is responsible for the red to pink colors in tomato, watermelon, red bell peppers, and pink guava. There are many health benefits attributed to lycopene including but not limited to its antioxidant activity. According to the American Lung Association’s State of Lung Cancer, lung cancer is still the leading cause of cancer death in the United States. Other chronic lung diseases such as asthma, emphysema, and chronic obstructive pulmonary disease are high prevalence. This chapter summarizes lycopene’s protective role against lung diseases in both in vitro and in vivo studies. While it has been demonstrated that circulating lycopene can be used as a biomarker for several lung diseases, further studies are warranted to establish that. We aim to provide insights into how lycopene can remedy for lung diseases, including lung cancer.


Lycopene: chemical definition and metabolism
Lycopene, a major dietary carotenoid pigment responsible for the red color, is synthesized by plants and microorganisms [1]. It is mostly found in tomatoes and tomato products, albeit there is a small amount of lycopene in few other fruits, including watermelon, papaya, guava, and pink grapefruit [2]. Lycopene is one of the six most abundant carotenoids (others being α-carotene, β-carotene, β-cryptoxanthin, lutein, and zeaxanthin) in circulation in humans [3]. It has been shown that lycopene exerts cancer-preventive or chemopreventive properties against several cancer types, including prostate, lung, and colon cancers [4].
Lycopene has a chemical formula of C 40 H 56 , tetraterpene comprised of eight isoprene units that are purely containing carbon and hydrogen [5]. Lycopene can undergo isomerization from trans to cis by heat, light, and chemical reactions, although the all-trans isomeric form is the main isomer in nature [6].

Lycopene: its antioxidant function
Lycopene is a linear, unsaturated hydrocarbon carotenoid with eleven and two unconjugated double bonds, making it highly reactive against oxygen and free radicals [10]. Lycopene displays the highest physical quenching rate constant of singlet oxygen (k q = 31 × 10 9 M −1 s −1 ) in vitro, while rate constants for α-carotene, β-carotene, and lutein were 19, 14, and 8, respectively [10]. Also, lycopene's antioxidant activity in liposomes was found to be greater than α-tocopherol [11]. It is worth highlighting its high quenching rate constant of singlet oxygen because lycopene's concentration in the circulation is 0.7 μM in humans. Lycopene can also scavenge hypochlorous acid, a precursor of free radicals in respiratory stress pathology [12]. It has been documented that tomato products with olive oil increased human plasma antioxidant activity [13]. The authors used the Ferric Reducing Antioxidant Power (FRAP) assay, a quantitative assay for measuring the antioxidant potential, to demonstrate the antioxidant activity of tomato products with olive oil, and it was increased from 930 to 1118 mmol/L [13]. Finally, lycopene could enhance the production of endogenous antioxidant enzymes, e.g., glutathione peroxidase (Gpx), glutathione reductase (GR), and superoxide dismutase (SOD) [14].

Lycopene: its dietary intake and bioavailability
Although lycopene can be consumed through various sources, processed tomato products (e.g., ketchup, tomato source, tomato juices, tomato extract) are the major dietary lycopene source in the United States [15]. Indeed, the mean lycopene content in these products is more than 90% [16]. The average lycopene intake in the U.S. is 6.6-10.5 mg/day in males and 5.7-10.4 mg/day in females [17].
Dietary lycopene intake amount is not always correlated with circulating lycopene levels because multiple factors can affect its bioavailability. Processed tomato products, for example, contain more lycopene than fresh fruits and vegetable [18]. While the lycopene content in ketchup is 9.9-13.44 mg lycopene/100 g [19], lycopene content in fresh tomatoes ranges from 1.82-11.9 mg/100 g wet weight [20]. Also, lycopene is more bioavailable in processed foods than in raw materials since the transformation of the all-trans isomer into the cis-isomer renders lycopene elevated solubility in bile acids [21,22]. Since lycopene is a lipid-soluble compound, a diet with high levels of lipids may increase lycopene bioavailability. It has been shown that the addition of avocado to salad significantly increased lycopene absorption in humans, although the increase of lycopene bioavailability was not correlated with avocado co-consumption in a dose-response manner [23].
The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org /10.5772/intechopen.95468 In a study with 33 subjects, researchers revealed that 72% of the variance in the postprandial plasma lycopene response was explained by 28 single nucleotide polymorphisms (SNPs) in 16 genes [24]. Among these genes, ATP binding cassette subfamily a member 1 (ABCA1), lipoprotein lipase (LPL), insulin-induced gene 2 (INSIG2), solute carrier family 27 member 6 (SLC27A6), lipase C (LIPC), cluster of differentiation 36 molecule (CD36), and apolipoprotein B (APOB) play critical roles in cellular lipid intake and transportation, indicating that the bioavailability of lycopene is likely to depend on lipid metabolism. Another study found that although SNP genotypes were unrelated to usual dietary lycopene intake, two BCO1 SNPs predicted the plasma lycopene changes after subjects were given the same amount of tomato juice [25]. Such finding is intriguing because the activity of BCO1 is lower than BCO2 toward non-provitamin A carotenoids such as lycopene [26], so further studies are warranted to explore the underlying mechanism by which BCO1 SNPs led to different postprandial lycopene response.
Lycopene is widely distributed in various tissues in humans. However, the distribution is uneven, with liver, adipose tissue, testes, adrenal glands, and circulating blood being the major storage pools [27,28] while lung and kidney have relatively low lycopene concentration [19]. It has been shown that familial resemblances were found in plasma lycopene, indicating that lycopene distribution variance is due to genetic and environmental factors [29]. Cigarette smoke, for example, decreased plasma carotenoid concentrations in humans [30,31]. A lower serum lycopene concentration was reported in ever-smokers than in never-smokers [32], and lycopene concentration was even substantially lower in smokers who take more than three cigarettes per day [33]. Other factors, including aging, air pollution, and the initiation of diseases such as cardiovascular disease and diabetes, may also deplete lycopene levels due to increased oxidative stress and elevated reactive oxygen species (ROS) [34,35]. While numerous studies reported the lycopene levels in patients with lung diseases, there is a gap in providing the overall picture. Therefore, our current work aims to shed light on the association between lung diseases and lycopene concentration and how lycopene supplementation affects lung disease initiation/development, offering further research directions.

Asthma
Asthma is characterized as the narrowing or blockage of the airways, leading to breathing difficulties like shortness of breath, coughing, or wheezing. The onset of asthma is associated with elevated pulmonary inflammation, which characteristically involves airway infiltration of related inflammatory cells through the activation of Th2-type lymphocytes, eosinophils, and mast cells [36]. A combination of these immunological activities with genetic and environmental factors can lead to the progression of asthma.
To investigate strategies to potentially mitigate the effects of asthma, two in vivo studies utilized dietary lycopene supplementation within a murine model induced with this lung condition. These studies involved intraperitoneal (i.p.) injection of ovalbumin (OVA) to induce airway inflammation in BALB/c mice and demonstrated that subsequent lycopene supplementation of 8 and 16 mg/kg body weight (BW)/day alleviated such inflammatory cell infiltration into the bronchoalveolar lavage fluid (BALF) [37] as well as into the lung tissue and blood supply [38].
Lycopene treatment at both of these dosages decreased the expression of eosinophil peroxidase (EPO) and the gelatinolytic activity of matrix metalloproteinase-9 (MMP-9) caused by the i.p. injection of OVA [37]. Lycopene administration at both dosages also inhibited the OVA-specific release of Th2-associated cytokines interleukin-4 (IL-4) and interleukin-5 (IL-5) [37,38]. The data presented in these studies revealed that dietary lycopene intervention could inhibit the infiltration of inflammatory immunocytes and alleviate asthma's pathogenesis and progression.

COPD and emphysema
Chronic obstructive pulmonary disease (COPD) is a coined term that governs a group of inflammatory lung conditions such as bronchiolitis and emphysema [39]. Bronchiolitis involves fibrosis-related obstruction of small air passages, while emphysema is characteristic of alveolar enlargement and alveolar wall damage. COPD symptoms commonly consist of a chronic cough, shortness of breath, excess phlegm or sputum, and chest tightness [40].
One of COPD's most prevalent risk factors is cigarette smoking, which can be usefully incorporated into in vivo studies to investigate potential remedies to alleviate proinflammatory symptoms and this chronic condition's progression. Due to its documented antioxidant capabilities, lycopene treatment can be utilized to reduce the oxidative stress induced by cigarette smoke. A study utilizing a ferret model investigated the efficacy of dietary lycopene stimulation upon both bronchiolitis and emphysema-related aspects of COPD [41]. Through i.p. injection of tobacco carcinogen nicotine-derived nitrosamine ketone (NNK) at 200 mg/kg BW/day and cigarette smoke exposure five days a week for four months, the COPD model was established in ferrets. Lycopene was administered via 10% w/w beadlets at a low dosage of 2.2 mg/kg BW/day and a high dosage of 6.6 mg/kg BW/day over 22 weeks. Following this exposure and treatment period, the findings illustrated that the high dose of lycopene decreased the incidence of NNK/cigarette smoke-induced bronchiolitis and emphysema in ferrets [41].
Tackling the issue of emphysema in particular, two in vivo studies investigated the antioxidant/anti-inflammatory efficacy of dietary lycopene supplementation on chronic cigarette smoke exposure alone in murine models. Lycopene administration at 25 and 50 mg/kg BW/day in C57BL/6 mice appeared to alleviate the detrimental effects of chronic cigarette smoke exposure (12 cigarettes/day) over 60 days [42]. Lycopene treatment at both dosages appeared to have improved redox balance and decreased lipid peroxidation and DNA damage; activities of SOD, catalase (CAT), and glutathione (GSH) were increased via lycopene treatment. Lycopene also decreased interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFNγ) levels at both dosages. On the other hand, the weight loss that occurred due to the smoke exposure was not recovered by lycopene treatment at either dosage. The same research team had previously conducted a short-term smoke exposure study [43] for just five days, not long enough to establish emphysema, that employed the same dosages of lycopene treatment (25 and 50 mg/kg BW/day). This earlier study described that lycopene administration decreased neutrophil initiation and macrophage influx into the BALF as well as similarly decreased levels of IL-10, TNF-α, and IFNγ at both dosages.
Another in vivo study investigated the association of age-related progression with emphysema development within a senescence-accelerated mouse (SAM) model [44]. Utilizing the SAM model that mimics the senile mouse lung, the study aimed to determine if the dietary lycopene supplementation could prevent the onset of emphysema through chronic cigarette smoke exposure (30 min/day, five days/week, for eight weeks). Tomato juice (containing 5 mg of lycopene) The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org /10.5772/intechopen.95468 administration in place of tap water was shown to have an inhibitory effect on the onset of cigarette smoke-induced emphysema.
Collectively, dietary lycopene supplementation appears to have alleviating effects upon chronic obstructive pulmonary disease, cigarette smoke-induced bronchiolitis, and emphysema due to its potent antioxidant and anti-inflammatory activities.

Acute lung injury
Acute lung injury (ALI) is an acute inflammatory pulmonary disorder that causes endothelial and epithelial barrier disruption, leading to compromised alveolar-capillary membrane integrity [45]. Factors such as lung infection, aspiration, sepsis, trauma, and shock can contribute to ALI's onset. Due to the loss of the alveolar-capillary membrane integrity, further complications characteristic of ALI can involve increased pulmonary edema permeability, increased infiltration of neutrophils, and increased release of pro-inflammatory cytotoxic mediators.
Several in vivo studies have been conducted utilizing dietary lycopene supplementation to determine potential treatment in alleviating the damage associated with acute lung injury. One method of generating ALI in these animals was through the administration of lipopolysaccharide (LPS). One study investigated the synergistic protective efficacy of lycopene and matrine, an alkaloid found in kinds of Sophora plants, against LPS-induced ALI compared to the corticosteroid dexamethasone (DEX) in BALB/c mice [46]. Mice were intraperitoneally injected with DEX (5 mg/kg BW), matrine (25 mg/kg BW), lycopene (100 mg/kg BW), or a combination of the matrine + lycopene treatments for seven days before a final dosage of LPS (5 mg/kg BW). Following 6 hours after LPS administration, the combined treatment of matrine and lycopene appeared to have similar beneficial effects. Furthermore, the combined treatment inhibited NF-κB p65 activity and reduced the expression of malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-6 (IL-6), and TNF-α while simultaneously upregulating GSH.
Sarcandra glabra (SG), an herb native to Southeast Asia which is used for treating various oxidative stress diseases, was incorporated within another study in conjunction with lycopene to combat LPS-induced ALI in a rat model [47]. The rats were treated similarly as the other study with supplementation of SG (2.5 mg/kg BW) and lycopene (5 mg/kg BW) individually or in combination for two weeks before LPS (6 mg/kg BW) administration. Like the study involving matrine, the combination of SG and lycopene led to a significant decrease in LPS-induced histopathological injuries, as well as reduced levels of IL-6, TNF-α, NF-κB, and mitogen-activated protein kinase (MAPK). Furthermore, the combination treatment increased antioxidative activity and helped reverse the abnormal metabolism back towards normal status. Courtesy of the findings from these studies, lycopene treatment has the potential to alleviate LPS-induced acute lung injury. As lipopolysaccharide is not the only way to induce acute lung injury, other studies have incorporated alternative methods to study lycopene's effect. A study investigated the effects of Redivio® capsules (lycopene in 10% fluid suspension) against oleic acid (OA)-induced ALI in Wistar rats [48]. Over five weeks, the rats were treated with 100 mg/kg BW/day OA and 20 mg/kg BW/day lycopene. Lycopene supplementation decreased neutrophilic infiltration and decreased perivascular and alveolar edema. Lycopene treatment also decreased serum and tissue MDA, serum and tissue SOD, and increased tissue CAT levels; however, there was no effect on serum and tissue Gpx. ALI can additionally be brought on by hyperoxia, which was investigated in a study involving newborn rats that were housed in conditions of normoxia (ambient air) or hyperoxia and supplemented with 50 mg lycopene in olive oil/kg BW/day for 11 days [49]. Despite the expected antioxidant effects of lycopene in these conditions, this treatment did not improve hyperoxia-induced injury as MDA, SOD, and IL-6 levels were not changed; interleukin-1β (IL-1β) and Gpx levels were not affected by hyperoxia or lycopene.

Pulmonary fibrosis
Lung fibrosis, or idiopathic pulmonary fibrosis (IPF), is considered an interstitial lung disease. It involves alveolar epithelial damage and scarring of the lungs due to excess deposition of extracellular matrix by myofibroblasts [50]. The alveolar epithelial degradation is considered an indicative initiating factor of IPF, and the associated damage can lead to interstitial pneumonia. Patients with IPF have a 20% higher risk of developing lung cancer, which can take approximately 2-4 years to reach end-stage respiratory insufficiency [51]. In this case, a treatment regime is quite crucial to shunt this detrimental progression.
Bleomycin (BLM), a polypeptide antitumor agent, can mimic lung fibrosis's pathological effects and can be incorporated within studies to study treatment efficacy. One in vivo study utilized this model via intratracheal instillation of BLM (4 mg/mL) in Sprague-Dawley rats to induce IPF [52]. Lycopene extracted from tomatoes was administered over 28 days at a dosage of 5 mg/kg BW/day appeared to alleviate the damage attributed to BLM-induced oxidative stress partially. Such lycopene treatment inhibited the extent of free radical injury, fibrosis, and alveolitis. Furthermore, supplemental lycopene decreased plasma and tissue levels of TNF-α and decreased plasma levels of MDA and nitric oxide (NO). Since lung fibroblasts can contribute to the onset of pulmonary fibrosis, this cell type can be studied within an in vitro context to identify methods of regulating their abnormal activity. Two in vitro studies capitalized on this cell line type by inducing DNA damage in Chinese lung fibroblasts, V79 cells, through peroxynitrite administration [53] and catechol estrogen [54]. The cells were pre-treated with β-carotene and lycopene at concentrations of 0-5 μM and 0-10 μM 24 hours before the damage. The treatment of these carotenoids decreased the DNA damage in these fibroblast cells by inhibiting single-strand breaks [53,54] and decreasing the inflammation oxidative stress [53].

Lung cancer
Lung cancer is the leading cause of cancer mortality in the United States, constituting nearly one fourth of all cancer deaths [55]; thus bringing about the need to finding remedies in any way possible. In terms of carotenoid treatment, supplementation of lycopene and its metabolites may demonstrate some anti-cancer efficacy within both in vitro and in vivo settings by inhibiting carcinoma severity and progression; such a trend has been seen in multiple cell types including prostate, breast, hepatoma, stomach, colon and oral cancer cells [56][57][58]. In the studies regarding lung cancer, the models typically involve lung cancer cell lines, cigarette smoke exposure, and the administration of carcinogenic agents. As non-small cell lung cancer (NSCLC) accounts for the most lung cancer-related deaths, various in vitro studies have utilized cell lines that characterize this cell type. In these cases, lycopene and its metabolites appeared to be a potent inhibitor of cancer cell growth and proliferation [59][60][61][62], even more so than either α-carotene or β-carotene [59], by arresting the cell cycle at the G1 checkpoint [62]. In cigarette smoke-induced oxidative stress, the formation of reactive oxygen species (ROS) could lead to damage of cellular macromolecules, notably to genomic DNA that can cause mutations. Like in the case of the Chinese hamster fibroblasts [50], lycopene's antioxidant potential was shown as its capability to quench ROS and upregulate enzymes related to base excision repair, such as DNA glycosylases [63].
Through the classic model of cancer-induction via cigarette smoke exposure in vivo, treatment of lycopene at both a low dose (1.1 mg/kg BW/day) and a high dose (4.3 mg/kg BW/day) for nine weeks reduced the extent of lung squamous metaplasia via apoptosis in a ferret model [64]. The apoptosis was attributed to the upregulation of plasma insulin-like growth factor binding protein-3 (IGFBP-3) levels and reduction of the IGF-1/IGFBP-3 ratio.
An alternate method of inducing tumorigenesis in animal models can be achieved through the administration of carcinogenic agents like benzo[a]pyrene (BaP), NNK, and dimethylhydrazine (DMH) [62][63][64]. An in vivo study utilized the DMH method of tumor-induction via subcutaneously injecting 20 mg/kg BW DMH into B6C3F1 mice, the F1 generation of a cross between C57BL/6 J females and C3H/HeJ males [65]. For 32 weeks, the mice were administered with DMH twice a week for five weeks and then lycopene (25 or 50 ppm in drinking water) starting at week 21. After this treatment period, anticancer effects were primarily seen in males as the high lycopene dose (50 ppm) decreased DMH-related tumor development and decreased multiplicities for lung adenomas and carcinomas [65]. Another two in vivo studies utilized the treatment of lycopene-enriched tomato oleserin (LTO) in models involving tumorigenesis induction via BaP only [66] or BaP and NNK [67]. In one of those particular studies, a proprietary MutaMouse model consisting of the F1 generation of a cross between BALB/c and DBA/2 mice was injected with 125 mg/kg BaP and treated with LTO (3.7% lycopene) at different doses in their diets (7 and 14 g LTO/kg diet, 0.5 and 1.0 mmol lycopene/kg diet). However, the BaP-induced lung mutagenesis was found to have increased with LTO supplementation, especially at the high dosage [66]. On the other hand, a study incorporating BaP and NNK-induced carcinogenesis into A/J mice investigated the effect of LTO (5.9% lycopene) at different doses in their diets (185 ppm, 1850 ppm, 9260 ppm). In this case, there was no overall effect on the weight gain or survivability of the mice; furthermore, none of the LTO-enriched treatments given before, during, or after BaP and NNK administration had any effect on tumor incidence or multiplicity [67]. The minimal or lack of effect that lycopene has on these carcinogenic agents may indicate that this carotenoid's anticancer efficacy is better suited against cigarette smoke exposure, possibly due to its antioxidant properties.
While lycopene is typically utilized within these carotenoid treatment studies, its metabolites have shown some anticancer efficacy, especially apo-10′-lycopenoic acid. In a joint in vitro and in vivo study, apo-10′-lycopenoic acid was shown to inhibit cell cycle progression in non-small cell lung cancer (NSCLC) and lung tumor multiplicity in A/J mice [62]. Approaching the in vitro aspect, normal human bronchial epithelial cells (NHBE), BEAS-2B-immortalized normal bronchial epithelial cells, and non-small cell lung cancer, A549 cells, were treated with 0-10 μM apo-10′-lycopenoic acid for five days; this treatment regime appeared to have decreased cyclin E and inhibited cell cycle progression from G1 to S phases as seen with lycopene previously [59]. Furthermore, cell cycle mediators (p21 and p27) were increased, indicating promoted mediation of checkpoint regulation.
Antioxidants -Benefits, Sources, Mechanisms of Action 8

Lycopene and lung diseases in human
To conclude the association between circulating lycopene and lung diseases, we performed a systematic review and meta-analysis by following the PRISMA guideline [72]. We conducted a comprehensive search of the following electronic databases: MEDLINE, Web of Science, EMBASE, and Google Scholar from inception up to November 8, 2020. We employed an integration of Medical Subject Heading (MeSH) terms and/or keywords to article-searching in these databases. The search terms are listed as follows: (

Eligibility
We used these inclusion criteria while carrying out a meta-analysis and systematic review: • patients with confirmed lung diseases including asthma, acute lung injuries, emphysema, COPD, lung fibrosis, and lung cancer; • used one of the following study designs: randomized controlled trial (RCT), cohort study, case-control study, nested case-control study, and crosssectional study; • reported circulating lycopene level, dietary lycopene intake, dietary consumption of lycopene-enriched foods (e.g., tomato products); • outcomes related to the incidence or development of lung diseases; • provided statistical reports When multiple studies included subjects from the same cohort, only the publication reported the most updated results were selected. In vitro studies and animal studies were excluded. Review articles were also excluded.

Data extraction
Data extraction was performed by two independent researchers (J. Cheng, A. Eroglu) by utilizing a structured form. A third investigator (E. Balbuena) would be involved if discrepancies occurred. The following information was collected from eligible studies: study characteristics (author, year of the study, study design, name of the cohort), subject characteristics (a type of lung disease, subject age), treatment information, and primary results, which included means, comparison of the groups, relative ratio (RR)/odds ratio (OR)/hazard ratio (HR), and the measure of variability (95% confidence interval and p-value). For studies that used both

Statistical analysis
We only included the studies that reported OR/RR/HR and 95% confidence interval to perform statistical analysis. Studies that failed to provide such information were excluded from meta-analysis but were still included in our systematic review with detailed information listed in Table 1. According to the rare disease assumption, the prevalence of lung diseases is low, and the relative risk approaches the odds ratio [73]. Therefore, we reported all risk estimates in our current metaanalysis as OR for simplicity. With the possibility that the variance between the studies was caused by heterogeneity, the pooled ORs of the risk of lung diseases were estimated using a random-effects model. Two-tailed p-values <0.05 were considered statistically significant. We performed statistical analyses by employing RevMan 5.4.1.

Results
The process of study selection was displayed in the flow chart (Figure 2). The search for the four databases yielded 105 articles, of which 101 were eventually screened (Figure 2). Forty-eight articles were included for final screening after we excluded 53 in vitro or animal studies. Among them, 11 articles were excluded with various rationales: the exposure is not lycopene-related (N = 1), outcomes are not related to lung diseases (N = 3), review articles (N = 3), full text unavailable (N = 1), or studies that used the same cohort (N = 4) which led to 37 papers included in this systematic review (Figure 2).
In total, eight case-control (including nested case-control) studies included 1,280 current asthma patients and explored circulating lycopene levels in cases versus matched controls. Additionally, one cross-sectional study with 218 subjects reported the association between serum lycopene concentration and asthma severity [77]. In four studies, a significantly lower circulating lycopene concentration was observed in cases than in healthy controls [76][77][78][79]. Nevertheless, other case-control studies reported similar circulating lycopene levels in asthma patients than the matched control group, indicating that the risk of asthma was unrelated to circulating lycopene levels [74,75,81,82]. Such discrepancy might be due to the heterogeneity of disease characteristics. Wood et al. showed a trend of higher plasma lycopene concentration in asthma patients with airway hyper-responsiveness [80]. It was also reported that plasma lycopene concentration was higher in atopic asthma subjects than in non-atopic asthma subjects [76]. Therefore, a high proportion of hyper-responsive asthma patients or atopic asthma patients may decrease the probability of observing a significant difference.
Two studies reported the correlation between circulating lycopene concentration and the severity of asthma. Forced expiratory volume in one second (FEV1) is defined as the volume of breath exhaled during a forced breath within one second.     Forced vital capacity (FVC) is the full air exhaled in the entire timeframe [87]. A low percentage predicted FEV1/FVC ratio is an indicator of reduced pulmonary function. Ochs-Balcom et al. reported a lack of association between serum lycopene concentration and %FEV1/FVC ratio in 22 asthma cases, indicating that circulating lycopene concentration is not correlated with pulmonary function [77]. Similarly, Wood et al. depicted that plasma lycopene concentration was similar in moderate asthma patients than patients with severe asthma [80]. Also, no difference was found in plasma lycopene levels between asthma controlled or partly controlled patients vs. uncontrolled patients [80], indicating that circulating lycopene levels are unrelated to asthma development. Four RCTs supplemented asthma patients with lycopene or lycopene-enriched foods to investigate the effect of dietary lycopene on asthma [83][84][85][86]. They   examined their pulmonary function at the end of the study [83][84][85][86]. Two studies addressed exercise-induced asthma, where researchers gave asthma patients lycopene at a dosage of 30 mg/d for one week [80,81]. Although one study found that lycopene supplementation increased %FEV1 [83], Falk et al. failed to observe any significant differences in pulmonary function indicators between patients with lycopene supplementation and the placebo group [84]. Such inconsistency may have resulted from the inadequate intensity of the exercise challenge in the study. In the study by Falk et al., the participants performed an eight-minute treadmill exercise at a load of 85% of the predicted maximal heart rate [84]. Such intensity may not be strenuous enough to induce exercise-induced bronchoconstriction, especially in physically active people [88]. Also, only 19 subjects were included in the trial, leading to a loss of power. Therefore, additional studies with larger samples size and higher exercise challenges are warranted to examine the effect of lycopene supplementation on exercise-induced asthma.

Author, Year
With a growing interest in investigating the synergistic effect of various antioxidants on lung diseases, Wood et al. provided the subjects with a 10-day low antioxidant diet, followed by either placebo or tomato extract (or tomato juice) supplementation that contains 45-mg lycopene for another ten days [85]. As a result, the low antioxidant diet significantly increased sputum neutrophils, decreased with tomato juice or tomato extract supplementation [85]. Furthermore, a reduced level of sputum neutrophil elastase activity was found in patients supplemented with tomato extract [85]. The neutrophil elastase released by neutrophils is a serine proteinase that may act as a biomarker of inflammation and pathogen invasion [89]. Since this enzyme is involved in lung tissue destruction, by inhibiting neutrophil elastase activity, tomato extract supplementation may hinder pulmonary inflammation, subsequently mitigate the swell of the airways and decrease mucus production [90], leading to alleviated asthma manifestations. Indeed, in a follow-up study with 137 subjects, Wood et al. portrayed decreased levels of plasma C-reactive protein (CRP), IL-6, and IL-1β in the asthma patients who consumed tomato extract that contains 45 mg/d lycopene [86]. Intriguingly, the repeated-measures analysis by time point showed a reduced risk of disease exacerbation in the patients with tomato extract supplementation compared to the placebo group. Additionally, the decrease of %FEV1 and %FVC from baseline was only observed in the placebo group, but not in the tomato extract-supplemented group [86].
Collectively, the results generated from these clinical trials did not show a consistent association between circulating lycopene and the initiation or development of asthma. Besides, there is a lack of evidence that dietary lycopene supplementation alleviating asthma progression. Whole foods that contain a high concentration of lycopene, such as tomato extract, showed beneficial efficacies against asthma. However, both RCTs subjects had a low-antioxidant diet at baseline to deplete their antioxidant levels, meaning that a similar alleviating effect may not be observed in people with normal circulating antioxidant concentrations. It is also important to note that tomato extract and tomato juice are high in lycopene and other antioxidants, such as ascorbic acid or β-carotene. Thus, lycopene itself may lack the capability of mitigating asthma. It should be noted that the combination of lycopene with other antioxidants produces a synergistic effect that can further inhibit pulmonary inflammation and lessen asthma manifestations.

COPD
Both asthma and COPD cause swelling in the airways and difficulties to breathe [91]. Several studies focused on tackling COPD and asthma-COPD overlap syndrome (ACOS) due to the similarities between the two diseases.
At the end of article screening, two case-control studies, one cross-sectional study, and one prospective study depicted the association between circulating lycopene concentration and COPD [75,77,81,92]. Overall, 105 COPD patients and 21 ACOS patients were included in the case-control studies [77,81], whereas the cross-sectional study included 218 subjects (68 asthma patients, 121 COPD patients, and 29 ACOS patients). The prospective study used the data from the Third National Health and Nutrition Examination Survey (NHANES III), recruiting 1,492 COPD patients [75].
In one case-control study, Kodama et al. reported a significantly lower plasma lycopene concentration in the COPD subjects than the healthy controls [81]. However, such an association was not observed in the ACOS subjects [81]. Interestingly, another case-control study did not find any differences in plasma lycopene levels between the COPD patients and the controls [92]. However, they demonstrated a positive correlation between plasma lycopene concentration and blood oxygenation saturation in COPD patients [92], indicating that circulating lycopene concentration may be related to COPD severity. Similarly, the crosssectional study conducted by Ochs-Balcom et al. also reported that serum lycopene concentration was positively associated with %FVC, but not %FEV1 or %FEV1/ FVC ratio [77]. In 2014, Ford et al. reported that although the COPD patients and the healthy controls appeared to have similar serum lycopene levels, they observed an inverse correlation between serum lycopene concentration and all-cause mortality among people with obstructive lung function [75]. With a large sample size and prospective study design, these findings highlighted the possibility that serum lycopene concentration could be a potential biomarker predicting COPD's development and prognosis.
Among the studies that reported the association between lycopene intake and lung cancer risk, nine studies provided detailed study estimates [95,96,[101][102][103][104][105][106]108] (Figure 3A). Our meta-analysis results showed that the meta-OR of lung cancer with a higher dietary lycopene intake was 0.79 (95% CI: 0.71-0.88, overall P < 0.0001). The p-value of the Chi-squared (Chi 2 ) test is 0.52, and the betweenstudy variance (I2) for lung cancer incidence is 0%, meaning that there was a minimum of heterogeneity in the studies. Two case-control studies found that lycopene or lycopene-enriched tomato juice's daily consumption was lower in lung cancer cases than in healthy controls [93]. In contrast, the Singapore Chinese Health Study failed to observe a significant correlation between lycopene dietary intake and lung cancer risk [109]. Multiple factors may contribute to the non-significant findings. In the case-control studies, studies that used the Food Frequency Questionnaire (FFQ ) to collect lycopene intake frequencies may undergo recall bias, which led to a loss of power. It is also likely to observe a significant difference in lycopene consumption between cases and controls by including subjects who had a low baseline circulating lycopene level or dietary lycopene intake. Rohan et al. observed significantly different lycopene intake between the cases and the controls when the subjects' daily lycopene intake was between 983 μg to 1,050 μg [102]. However, by including the subjects who reported a baseline daily dietary lycopene intake at 15.8 mg to 16.9 mg, which is about twice the amount of average daily lycopene intake in the U.S. [17], Shareck et al. found the dietary lycopene intake was comparable between the cases and the controls [104].
Three case-control studies [93, 99,107] and three nested case-control studies [32,94,97] reported the association between circulating lycopene concentration and lung cancer risk. Two studies provided estimates [32,98], thus were included in the meta-analysis. Since Ito et al. only reported the estimates in the male and female subgroups [98], we pooled the two subgroups and another study [32] to explore the relationship between circulating lycopene concentration and lung cancer risk by performing the meta-analysis. Our results showed that the meta-odds ratio of lung cancer with a higher circulating lycopene level was 0.47 (95% CI: 0.30-0.73, overall P = 0.0007), with the Chi 2 p-value at 0.84, and the I2 at 0% (Figure 3B). Such data indicates that a higher circulating level of lycopene is correlated with a lower risk of lung cancer. Intriguingly, the other three studies that were not included in the meta-analysis consistently showed that lung cancer cases had a significantly lower circulating lycopene concentration than the healthy controls [93, 99,110]. Only one study reported a similar lycopene concentration in lung cancer subjects and the controls [94]. One possible explanation for this negative result is that Comstock et al. did not stratify the subjects according to the stage of lung cancer. Although serum lycopene concentration was comparable in the early stage patients and the advanced stage patients, serum lycopene concentration was more significant between the advanced lung cancer patients and the healthy controls [99]. If the majority of the patients included by Klarod et al. were cancer patients at an early stage, the difference of circulating lycopene level between the cases and the controls would be unapparent. One prospective study showed that serum lycopene concentration was lower in the lung cancer deaths than in the cancer survivors; however, such difference disappeared after the researchers adjusted the model for sex, age, smoking habit, and serum levels of total cholesterol and alanine aminotransferase (ALT) activity [97] suggesting that the association between lycopene and lung cancer mortality might be influenced by multiple factors, which warrants further investigation.
In conclusion, we found consistent reports showing that dietary lycopene intake, or the consumption of lycopene-enriched foods, was inversely related to lung cancer risk. Our systematic review and meta-analysis showed that the circulating lycopene level might be a potential biomarker predicting lung cancer risk.

Concluding remarks
We summarized the association between circulating lycopene and chronic lung diseases in a comprehensive manner. To accomplish this task, we first have screened both in vitro reports and in vivo animal models to delineate lycopene's role in chronic lung diseases including asthma, COPD, emphysema, acute lung injury, pulmonary fibrosis, and lung cancer. Dietary lycopene intervention could potentially decrease the infiltration of pro-inflammatory cytokines in ovalbumin-induced airway inflammation in a murine model of asthma [37,38]. Lycopene was also found to inhibit smoke-induced bronchitis and emphysema through reverse cholesterol transport in the COPD model in ferrets [41]. In a murine model (C57BL/6 mice) for emphysema, lycopene administration lessened the detrimental effects of chronic cigarette smoke exposure [42]. Lycopene treatment was found to ease LPS-induced acute lung injury (ALI) in murine animal models [46], BALB/c mice, and LPSinduced ALI in a rat model [47]. Lycopene extracted from tomatoes could reduce the burden of lung fibrosis's pathological effects in a rodent study [52]. In terms of lung cancer, lycopene could decrease the extent of squamous metaplasia in a ferret model using the conventional method of induction of lung cancer by cigarette smoke [64]. Alternative models using carcinogenic agents were not definitive in showing its chemoprevention capabilities [62][63][64][65][66][67].
Next, we conducted a systematic review and meta-analysis to reveal the link between lycopene concentration and lung diseases in clinical trials using multiple electronic databases. While several case-control studies reported markedly lower lycopene concentration in asthma patients [76][77][78][79], others found that asthma progression was not related to lycopene in the circulation [74,75,77,[80][81][82], suggesting that the association between asthma and lycopene concentrations in humans was not conclusive. We came across several epidemiological studies, including casecontrol, cross-sectional, and prospective studies, to demonstrate the association between lycopene concentration in the circulation and COPD in our meta-analysis. These trials reported similar lycopene concentrations in healthy subjects vs. COPD patients [75,77,81,92]. Finally, we found that dietary lycopene is inversely associated with lung cancer risk, particularly in subjects with low lycopene in their circulation [93, 102,104]. Furthermore, circulating lycopene displayed a significant association between advanced lung cancer patients and early-stage patients [99].

Future perspective
Overall, our comprehensive review in this chapter provides convincing evidence on the role of lycopene in chronic lung diseases including lung cancer. This chapter also contributes confirmatory data to the as yet unsettled proof on the hypothesized associations between lycopene in circulation and lung diseases. The health benefits of lycopene can be attributed to its antioxidant function as highlighted in this chapter. Lycopene can be used as a preventive and therapeutic compound by itself or in combination with other compounds to improve lung diseases. Further investigations and well-designed clinical trials are needed to confirm whether there is a casual relation between the disease and the circulating lycopene in humans.