The Role of Lycopene in Chronic Lung Diseases

*Emilio Balbuena, Junrui Cheng and Abdulkerim Eroglu*

## **Abstract**

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.

**Keywords:** lycopene, lung diseases, oxidative stress, lung cancer, antioxidants, carotenoids

## **1. Introduction**

### **1.1 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 C40H56, 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 can be cleaved via two pathways (**Figure 1**). It can be metabolized by central cleavage, catalyzed by beta-carotene-15,15′-oxygenase (BCO1), yielding apo-15′-lycopenal [7]. It also can be metabolized by eccentric cleavage, catalyzed by beta-carotene-9′,10′-oxygenase (BCO2) yielding apo-10′-lycopenal, which can be either further oxidized into apo-10′-lycopenoic acid or reduced to apo-10′ lycopenol [8]. It has also been shown apo-lycopenals at various chain lengths can also be derived from the absorption of apo-lycopenals directly from food [9].

#### **Figure 1.**

*Central and eccentric cleavage of lycopene. Oxidative cleavage of lycopene at the central 15, 15*′ *double bond is catalyzed by beta-carotene-15,15*′*-oxygenase 1 (BCO1) leading to the generation of two molecules of apo-15*′ *lycopenal [7]. Eccentric cleavage takes place at the 9*′*-10*′ *double bond and is catalyzed by beta-carotene-9, 10*′*-oxygenase 2 (BCO2) yielding apo-10*′*-lycopenal [8].*

#### **1.2 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 × 109 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].

#### **1.3 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].

There has been growing research interest in genetic variant studies in recent years and the association between genetic variation and lycopene bioavailability.

**199**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

SNPs led to different postprandial lycopene response.

initiation/development, offering further research directions.

**2. Lycopene and lung diseases**

**2.1** *In vitro* **and** *in vivo* **evidence**

the progression of asthma.

*2.1.1 Asthma*

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

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

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

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].

#### *The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**1.2 Lycopene: its antioxidant function**

*10*′*-oxygenase 2 (BCO2) yielding apo-10*′*-lycopenal [8].*

**1.3 Lycopene: its dietary intake and bioavailability**

singlet oxygen (*k*q = 31 × 109

(SOD) [14].

**Figure 1.**

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

*Central and eccentric cleavage of lycopene. Oxidative cleavage of lycopene at the central 15, 15*′ *double bond is catalyzed by beta-carotene-15,15*′*-oxygenase 1 (BCO1) leading to the generation of two molecules of apo-15*′ *lycopenal [7]. Eccentric cleavage takes place at the 9*′*-10*′ *double bond and is catalyzed by beta-carotene-9,* 

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

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].

There has been growing research interest in genetic variant studies in recent years and the association between genetic variation and lycopene bioavailability.

U.S. is 6.6–10.5 mg/day in males and 5.7–10.4 mg/day in females [17].

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

M−1 s−1) *in vitro*, while rate constants for α-carotene,

**198**

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.

## **2. Lycopene and lung diseases**

## **2.1** *In vitro* **and** *in vivo* **evidence**

## *2.1.1 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.

#### *2.1.2 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)

**201**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

activities.

*2.1.3 Acute lung injury*

onset of cigarette smoke-induced emphysema.

administration in place of tap water was shown to have an inhibitory effect on the

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

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 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.

#### *2.1.3 Acute lung injury*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

phlegm or sputum, and chest tightness [40].

chiolitis and emphysema in ferrets [41].

decreased levels of IL-10, TNF-α, and IFNγ at both dosages.

*2.1.2 COPD and emphysema*

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.

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

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 bron-

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

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)

**200**

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.

### *2.1.4 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].

#### *2.1.5 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 [56–58]. 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 [59–62], 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

**203**

connexin-43 (Cx43) [63, 71].

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

tion of the IGF-1/IGFBP-3 ratio.

to base excision repair, such as DNA glycosylases [63].

potential was shown as its capability to quench ROS and upregulate enzymes related

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 reduc-

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) [62–64]. 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.

Lycopene also appears to be involved in tumorigenesis suppression through several pathways, such as inhibiting NF-κB, activating sirtuin-1, or modulating reverse cholesterol transport mechanism by inhibiting 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase expression [1, 68, 69]. Furthermore, lycopene and its metabolites have been shown to upregulate retinoic acid receptor β (RARβ) activation [63], leading to reduced cell proliferation, increased apoptosis [70], and enhanced gap junction communication (GJC) by upregulating

#### *The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

quite crucial to shunt this detrimental progression.

lycopene.

*2.1.4 Pulmonary fibrosis*

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

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

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

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 [56–58]. 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 [59–62], 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

**202**

stress [53].

*2.1.5 Lung cancer*

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) [62–64]. 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.

Lycopene also appears to be involved in tumorigenesis suppression through several pathways, such as inhibiting NF-κB, activating sirtuin-1, or modulating reverse cholesterol transport mechanism by inhibiting 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase expression [1, 68, 69]. Furthermore, lycopene and its metabolites have been shown to upregulate retinoic acid receptor β (RARβ) activation [63], leading to reduced cell proliferation, increased apoptosis [70], and enhanced gap junction communication (GJC) by upregulating connexin-43 (Cx43) [63, 71].

## **3. 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:

("lung diseases"[MeSH Terms (MeSH), title or abstract (ti/ab)] OR (("lung"[MeSH] OR "lung"[All Fields]) AND "cancer\*"[MeSH Terms]) OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR ("pulmonary emphysema"[MeSH, ti/ab] OR "emphysema"[MeSH, ti/ab]) OR "asthma"[MeSH, ti/ab] OR "acute lung injur\*"[MeSH] OR "cystic fibrosis"[MeSH, ti/ab] OR "pulmonary fibrosis"[MeSH, ti/ab]) AND "lycopene"[MeSH, ti/ab].

## **3.1 Methods**

## *3.1.1 Eligibility*

We used these inclusion criteria while carrying out a meta-analysis and systematic review:


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.

## *3.1.2 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

**205**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

included in this systematic review (**Figure 2**).

*3.1.3 Statistical analysis*

RevMan 5.4.1.

**3.2 Results**

*3.2.1 Asthma*

trials (RCTs) [83–86].

univariate analysis and multivariate analysis, only the multivariate analysis results

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

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

A total of 13 articles reported the relation between asthma and lycopene concentration, or dietary lycopene intake [74–86]. Among them, 9 studies are observational studies: cross-sectional (N = 1), nested case–control (N = 1), or case–control studies (N = 7) [74–82], whereas other studies are randomized clinical

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 [76–79]. 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

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.

decrease the probability of observing a significant difference.

were extracted. A table was constructed (**Table 1**) to summarize the data.

univariate analysis and multivariate analysis, only the multivariate analysis results were extracted. A table was constructed (**Table 1**) to summarize the data.

## *3.1.3 Statistical analysis*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**3. Lycopene and lung diseases in human**

terms are listed as follows:

**3.1 Methods**

*3.1.1 Eligibility*

sectional study;

*3.1.2 Data extraction*

• provided statistical reports

review:

ti/ab]) AND "lycopene"[MeSH, ti/ab].

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

("lung diseases"[MeSH Terms (MeSH), title or abstract (ti/ab)] OR (("lung"[MeSH] OR "lung"[All Fields]) AND "cancer\*"[MeSH Terms]) OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR "pulmonary disease, chronic obstructive"[MeSH, ti/ab] OR ("pulmonary emphysema"[MeSH, ti/ab] OR "emphysema"[MeSH, ti/ab]) OR "asthma"[MeSH, ti/ab] OR "acute lung

injur\*"[MeSH] OR "cystic fibrosis"[MeSH, ti/ab] OR "pulmonary fibrosis"[MeSH,

We used these inclusion criteria while carrying out a meta-analysis and systematic

• patients with confirmed lung diseases including asthma, acute lung injuries,

• used one of the following study designs: randomized controlled trial (RCT), cohort study, case–control study, nested case–control study, and cross-

• reported circulating lycopene level, dietary lycopene intake, dietary consump-

When multiple studies included subjects from the same cohort, only the publication reported the most updated results were selected. *In vitro* studies and animal

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

emphysema, COPD, lung fibrosis, and lung cancer;

tion of lycopene-enriched foods (e.g., tomato products);

studies were excluded. Review articles were also excluded.

• outcomes related to the incidence or development of lung diseases;

**204**

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.

## **3.2 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**).

## *3.2.1 Asthma*

A total of 13 articles reported the relation between asthma and lycopene concentration, or dietary lycopene intake [74–86]. Among them, 9 studies are observational studies: cross-sectional (N = 1), nested case–control (N = 1), or case–control studies (N = 7) [74–82], whereas other studies are randomized clinical trials (RCTs) [83–86].

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 [76–79]. 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.


**207**

**Author, Year** Ochs- Balcom, 2006 Jun, 2020 Ford, 2014

Ito, 2005 Stefani, 1993

Lung cancer

Case–control

541

30–89

NA

NA

• • •

Lung cancer

Prospective

3,182

39–79

NA

10.5 years

• P = 0.007)

•

Serum lycopene concentration was unrelated to lung cancer

mortality (HR = 0.93, 95% CI: 0.39–2.24, P trend = 0.76)

Lycopene intake was similar in cases vs. controls

(1603.4 ± 1416 μg/d vs. 1666.6 ± 1439 μg/d, P = 0.47)

Dietary lycopene intake was unrelated to lung cancer risk

(OR = 0.83, 95% CI: 0.56–1.21, P trend = 0.18)

A higher dietary tomato intake frequency was correlated

with lower lung cancer risk (OR = 0.76, 95% CI: 0.55–1.07, P

trend = 0.09)

study

COPD

Prospective

1,492

55.7 ± 0.7

NA

14 years

• •

study

Pulmonary

Crosssectional

15,792

54.1 ± NR

NA

NA

• •

Lycopene dietary intake was not correlated with FEV1/FVC ratio (P = 0.283)

The consumption of lycopene & lutein/zeaxanthin foods were

not correlated with FEV1/FVC ratio (P = 0.518)

Serum lycopene concentration was similar in cases vs. controls

(0.41 ± 0.03 μmoL/L vs. 0.46 ± 0.01 μmoL/L, P = 0.120)

A higher serum lycopene concentration was correlated with a

lower all-cause mortality among adults with obstructive lung

function (HR = 0.80, 95% CI: 0.67–0.95, P = 0.013)

Serum lycopene concentration was lower in lung cancer deaths

vs. the survivors (0.229 ± NR μmoL/L vs. 0.328 ± NR μmoL/L,

function

Asthma COPD

Cross- sectional

• 68 asthma patients • 121 COPD patients • 29 asthma and COPD patients

61.7 ± 10.3

NA

NA

• • and %FEV1/FVC (P 0.05)

Serum lycopene was positively associated with %FVC (P 0.05)

Dietary lycopene intake was positively associated with %FEV1

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age (mean,yr)\***

**Treatment**

**Duration**

**Results**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*


## *The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**206**

**Author,** 

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age** 

**Treatment**

**Duration**

**Results**

**(mean,yr)\***

**Year**

Rohan, 2002

Sackesen,

Asthma

Case–control

164

9.65 ± 1.55

NA

NA

•

Plasma lycopene concentration was higher in children with

atopic asthma vs. non-atopic asthma (0.46 ± 0.2 μmoL/L vs.

0.45 ± 0.2 μmoL/L, P = 0.027)

• (P < 0.001)

Plasma lycopene concentration was lower in cases vs. controls

2008

Voorrips,

Lung cancer

Nested

939

55–69

NA

6.3 years

• •

Lycopene intake was lower in cases than in controls

(983 ± 1517 μg/d vs. 1050 ± 1560 μg/d, P = NR)

A lower lycopene intake was correlated with higher lung cancer

risk (RR = 1.12, 95% CI: 0.77–1.71, P trend = 0.04). However,

after adjusted for folate intake, the correlation was not statistically significant (RR = 1.05, 95% CI: 0.75–1.46, P trend = 0.14)

case–control

2000

Wood, 2005

Kodama,

Asthma-COPD overlap

Case–control

• 39 COPD

• 72.7 ± 6.9

NA

NA

• controls (P 0.05)

• healthy controls (P > 0.05)

• healthy controls (P > 0.05)

Plasma lycopene concentration was similar in BA subjects vs.

Plasma was lycopene concentration similar in ACOS subjects vs.

Plasma lycopene concentration was lower in COPD subjects vs.

(COPD)

• 66.8 ± 8.4

(ACOS)

• 56.4 ± 13.7

(BA)

patients

• 21 patients

with ACOS

(asthma-COPD

overlap

syndrome)

• 15 patients

with BA

(bronchial

asthma)

Schock,

Asthma

Case–control

78

7.2 ± 3.3

NA

NA

Lycopene concentration in the BAL was similar between cases vs.

controls (0.146 μmoL/L vs. 0.156 μmoL/L, P = 0.33)

2003

syndrome

Bronchial

asthma

2015

Asthma

Case–control

15

48.4 ± 4.3

NA

NA

• P > 0.05)

• vs. 2.51 mg/d, P > 0.05)

Daily lycopene intake was similar in cases vs. controls (3.90 mg/d

Cases had a lower lycopene level vs. controls in whole blood (29

ug/L vs. 247 ug/L P 0.05) or whole sputum (31 ug/L vs. 9 ug/L,

Lung cancer

Nested

196

40–59

NA

8

Lycopene intake was unrelated to lung cancer risk (RR = 1.04, 95%

CI: 0.61–1.76, P trend = 0.233)

case–control


**209**

**Author, Year** Shareck, 2017 Satia, 2009

Lung cancer

Prospective study

521

67.0 ± 6.8

NA

3 years

• •

Lycopene supplementation frequency was similar between

NSCLC cases vs. controls (multivitamin use: HR = 1.14, 95% CI:

0.90–1.44; individual supplement use: HR = 1.32, CI 0.33–5.30,

P trend = 0.25)

• •

Lycopene supplementation frequency was similar between

SCLC cases vs. controls (multivitamin use: HR = 0.97, 95% CI:

0.55–1.71; individual supplement use data NR, P trend = 0.81)

Lycopene supplementation frequency was similar between other

lung cancer cases vs. controls (multivitamin use: HR = 0.67,

95% CI: 0.33–1.37; individual supplement use data NR, P

trend = 0.24)

Ito, 2005

Lung cancer

Nested

211

40–79

NA

10 years

•

In male, serum lycopene concentration was lower in cases vs.

controls (0.06 μmoL/L vs. 0.07 μmoL/L, Univariate model:

P = 0.025; Multivariate model: P = 0.032)

In female, serum lycopene concentration was similar in cases

vs. controls (0.10 μmoL/L vs. 0.412 μmoL/L, Univariate model:

P = 0.20; Multivariate model: P = 0.33)

•

In male, a higher serum lycopene concentration was correlated

with a lower lung cancer risk (OR = 0.44, CI 0.19–1.05, P

trend = 0.03)

•

In female, serum lycopene concentration was unrelated to lung

cancer risk (OR = 0.82, CI 0.12–3.25, P trend = 0.5)

•

case–control

Lung cancer

Case–control

1,105

64.3 ± 7.8

NA

NA

Dietary lycopene intake was lower in cases vs. control (male: 15,888 ± 10,878 vs. 16,969 ± 9,285, P: NR; female: 11,911 ± 11,902 vs. 16,175 ± 10,985, P: NR)

A higher lycopene intake was correlated with a lower lung cancer risk (OR = 0.75, 95% CI: 0.59–0.95, P = 0.03)

Lycopene supplementation frequency was similar between total lung cancer cases vs. controls (multivitamin use: HR = 1.06, CI 0.86–1.30; individual supplement use: HR = 0.98, 95% CI: 0.25–3.96, P trend = 0.61)

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age (mean,yr)\***

**Treatment**

**Duration**

**Results**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*


*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**208**

**Author,** 

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age** 

**Treatment**

**Duration**

**Results**

**(mean,yr)\***

**Year**

Holick, 2002

Yuan, 2003

Asbaghi,

Lung cancer

Case–control

55

NR

NA

NA

• (P = 0.001)

• controls (P = 0.004)

Serum lycopene concentration was lower in cases than in

Plasma lycopene concentration was lower in cases than in controls

(<0.02 ± NR μmoL/L vs. 0.37 ± NR μmoL/L, P < 0.001)

Lycopene supplementation did not change FVC, predicted %FVC,

FEV1, predicted %FEV1, PEF1, predicted %PEF1, FEF25–75, or

predicted %FEF25–75 (P values were NR) among subjects who had

exercise-induced asthma

Dietary lycopene intake was unrelated to lung cancer risk (OR = 0.56, 95% CI: 0.26–1.24, P trend = 0.15)

Daily lycopene intake was lower in cases than in controls

2015

Talwar, 1997

Falk, 2005 Garcia-Closas, 1998

Michaud,

Lung cancer

Prospective

46,924 men

NR

NA

10 years

•

Lycopene intake was unrelated to lung cancer in males

(RR = 0.86, 95% CI: 0.59–1.25, P = 0.51) or females (RR = 0.80,

(men)

12 years

95% CI: 0.64–0.99, P = 0.10)

(women)

•

In lag analysis, lycopene intake was not correlated with lung

cancer risk (0–4-y lag: RR = 0.93, 95% CI: 0.76–1.15; 8–12-y

lag: RR = 0.87, 95% CI: 0.61–1.24), except for in 4–8-y lag

(RR = 0.68, 95% CI: 0.53–0.88)

77,283

women

study

2000

Lung cancer

Case–control

103

63

NA

NA

Asthma

RCT

19

13.0 ± 2.15

Placebo

1 week

Lycopene

(30 mg/d)

Lung cancer

Case–control

22

66

NA

NA

Lung cancer

Prospective

63,257

63 ± NR

NA

8 years

study

Lung cancer

Prospective

27,084

57.2

NA

14 years

•

A higher dietary lycopene intake was correlated with lower lung

cancer risk (Age-adjusted: RR = 0.63, CI 0.54–0.75, P trend

<0.0001; Multivariate: RR = 0.72, 95% CI: 0.61–0.84, P trend

<0.0001)

•

In subgroup analysis, a higher lycopene intake was correlated

with lower lung cancer risk in subjects who took 5–19 cigarettes

(RR = 0.65, 95% CI: 0.49–0.87, P for trend = 0.01), 20–29 cigarettes (RR = 0.81, 95% CI: 0.64–1.02, P for trend = 0.009), ≥30

cigarettes (RR = 0.63, 95% CI: 0.45–0.88, P for trend = 0.008)

Lycopene dietary intake was unrelated to lung cancer risk

(RR = 0.89, 95% CI: NR, P trend: NR)

study


**211**

**Author, Year** Riccioni, 2007 Riccioni,

Asthma

Case–control

22

35.1 ± 11.7

NA

NA

2006

Yuan, 2001 Wood, 2010

Asthma

Case–control

41

49 ± 3.4

NA

NA

•

There was a trend of higher plasma lycopene concentration in

hyper-responsive asthma patients vs. non-hyper-responsive

asthma patients (0.115 ± 0.45 mg/L vs. 0.084 ± NR mg/L,

P = 0.098)

•

Plasma lycopene concentration was similar in patients with

asthma controlled or partly controlled vs. uncontrolled

(0.10 mg/L vs. 0.08 mg/L, P = 0.581)

•

Plasma lycopene concentration was similar in patients with

mild–moderate asthma vs. severe asthma (0.10 mg/L vs.

Lycopene supplementation increased forced expiratory volume in

1 s among patients who had exercise-induced asthma (P < 0.05)

0.09 mg/L, P = 0.862)

Neuman,

Asthma

RCT

20

23 ± 9

Placebo

1 week

Lycopene

(30 mg/d)

2000

Lung cancer

Nested

209

64.8 ± NR

NA

12 years

• •

A higher serum lycopene concentration was correlated with

lower lung cancer risk in all subjects (OR = 0.46, 95% CI:

0.27–0.79, P trend = 0.003), but the adjusted OR was not statistically significant (OR = 0.15, 95% CI: 0.31–1.14, P = 0.15)

case–control

Asthma

Case–control

40

37.1 ± 12.5

NA

NA

•

Tomato intake was similar in the cases vs. controls (raw toma-

toes: 18.1 g vs. 16.8 g, P > 0.05)

•

Serum lycopene was lower in cases vs. controls (0.10 ± 0.7

μmoL/L vs. 0.16 ± 0.8 μmoL/L, P < 0.001)

Plasma lycopene concentration was lower in asthma patients vs.

controls (8.12 ± 2.63 lg/dl vs. 18.13 ± 3.67 lg/dl, P < 0.001)

Serum lycopene concentration was lower in ever-smokers than

in never-smokers (P = 0.0002)

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age (mean,yr)\***

**Treatment**

**Duration**

**Results**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*


## *The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**210**

**Author,** 

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age** 

**Treatment**

**Duration**

**Results**

**(mean,yr)\***

**Year**

Wood, 2008

Asthma

Randomized,

32

52.1 ± 2.4

Low

• 10 days

•

Low antioxidant diet: ↓ predicted %FEV1 (P = 0.004), %FVC

(P = 0.0032), asthma control score (P = 0.0035), sputum %neutrophils (P = 0.038), %macrophages (P = 0.06); unchanged

biomarkers including FEV1/FVC (P = 0.407), sputum PD15

(P = 0.838), total cell count (P = 0.401), %eosinophils

(P = 0.894), exhaled nitric oxide (P = 0.975), and neutrophil

of low

antioxidant

antioxidant

diet then

placebo,

diet

• 7 days

for each

treatment

elastase (P = 0.961)

• 10 days

•

Tomato juice supplementation ↓ sputum %neutrophils (P 0.05)

Tomato extract supplementation ↓ sputum %neutrophils

(P < 0.05) and neutrophil elastase activity (P < 0.05)

Tomato extract supplementation ↓ plasma CRP (P = 0.010), IL-6

for each

washout

•

or tomato

extract (45 mg

lycopene/

day), or

tomato

juice (45 mg

lycopene/day)

Wood, 2012

Asthma

RCT

137

Highantioxidant

Lowantioxidant

14 weeks

•

or until an

(P = 0.093), TNF-a (P = 0.070)

exacerbation

•

Tomato extract supplementation did not change %FEV1

(P = 0.948), %FVC (P = 0.534), %FEV1/%FVC (P = 0.918), DRS

(P = 0.954), ACQ (P = 0.597), exhaled NO (P = 0.296), sputum

%eosinophils (P = 0.299), eosinophil count (P = 0.384), IL-8

(P = 0.874), NE (P = 0.968), or 8-isoprostane (P = 0.720)

occurred

diet (54 ± 14)

diet (<=2

servings of

vegetables

and 1 serving

of fruit/day),

then placebo

or lycopene

(45 mg/d)

Larkin, 2015

Kentson,

COPD

Case–control

66

70 ± NR

NA

NA

• •

Plasma lycopene concentration was similar between cases vs.

controls (0.41 ± 0.20 μmoL/L vs. 0.48 ± 0.21 μmoL/L, P > 0.05)

Plasma lycopene concentration was positively correlated with

blood oxygenation saturation in the COPD patients (P < 0.05)

2018

Asthma

Nested

150

52.5 ± 8.7

NA

8 years

• •

Plasma lycopene concentration was not correlated with asthma

risk (OR = 0.9w6; 95% CI, 0.84–1.11)

Plasma lycopene concentration was similar in cases vs. controls

(6.8 mg/dl vs. 6.7 mg/dl, P = 0.79)

case–control

Lowantioxidant diet (58 ± 14)

cross-over

trial


**213**

**Author, Year** Schut, 1997

Kawchak, 1999

Cystic fibrosis

Nested case–control

24

NR

3 years

Standard nutrition care and vitamin supplements that included 5,000 IU retinol

*A table was constructed to summarize the data of clinical trials including 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.*

*\*Significance values presented individually in each study's result column.*

**Table 1.**

Lung cancer

Case–control

19

NR

NA

NA

Serum lycopene concentration was lower in lung cancer patients vs. controls (0.13 ± 0.10 μmoL/L vs. 0.42 ± 0.41 μmoL/L, P < 0.01)

At the baseline, serum lycopene concentration was lower in cases vs. controls (0.05 ± 0.05 μmoL/L vs. NR, range 0.15–0.39 μmoL/L, P 0.05).

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age (mean,yr)\***

**Treatment**

**Duration**

**Results**

*The Role of Lycopene in Chronic Lung Diseases DOI: http://dx.doi.org/10.5772/intechopen.95468*

