**Table 1.**

*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.*

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

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**212**

**Author,** 

**Lung disease**

**Study Design**

**Subject (N\*)**

**Age** 

**Treatment**

**Duration**

**Results**

**(mean,yr)\***

**Year**

Ford, 2004

Asthma

Case–control

• 771 current

• 44.8 ± 0.7

NA

NA

• μmoL/L)

• μmoL/L)

Plasma lycopene concentration was similar between former

asthma patients vs. controls (0.47 ± 0.04 μmoL/L vs. 0.44 ± 0.00

Plasma lycopene concentration was similar between current

asthma patients vs. controls (0.44 ± 0.01 μmoL/L vs. 0.44 ± 0.00

(current

asthma)

• 44.2 ± 1.0

(former

asthma)

Klarod, 2011

Comstock,

Lung cancer

Nested

258

25–65

NA

15 years

•

Serum lycopene concentration was similar in cases vs. controls

(CLUE I)

(P = 0.76)

3 years

• •

Serum lycopene concentration was unrelated to lung cancer risk

(OR = 1.01, 95% CI: NR, P trend = 0.99)

In subgroup analysis, serum lycopene concentration was

unrelated to lung cancer risk (Male: OR = 0.32, 95% CI: NR, P

trend = 0.25; Female: OR = 0.83, CI NR, P trend = 0.83)

A lower tomato (including tomato juice) intake was correlated

with higher lung cancer risk in males (OR = 2.3, 95% CI: NR,

P trend = 0.002) and females (OR = 3.7, 95% CI: NR, P trend

<0.001)

(CLUE II)

case–control

2008

Marchand,

Lung cancer

Case–control

332

NR

NA

NA

•

1989

Steinmetz,

Lung cancer

Nested

138

55–69

NA

4 years

• •

The consumption of the 'high-lycopene' foods was unrelated to

lung cancer risk (OR = 1.21, 95% CI: 0.69–2.10, P trend = 0.53)

Tomato consumption was unrelated to lung cancer risk

(OR = 1.00, 95% CI: 0.61–1.64. P trend = 0.99)

case–control

1993

Lung cancer

Case–control

49

58.8 ± NR

NA

NA

• controls (P < 0.001)

• in controls.

•

Serum lycopene concentration was similar in early stage patients

vs. advanced stage patients (P = 0.749)

Serum lycopene concentration was lower in both early stage

patients (P = 0.09) and advanced stage patients (P = 0.001) than

Serum lycopene concentration was lower in total cases than in

asthma

• 352 former

asthma

#### **Figure 2.**

*Flow diagram of study selection according to the PRISMA guideline.*

#### **Figure 3.**

*Forest plots for lung cancer risk in (A) subjects with lower lycopene intake vs. subjects with higher lycopene intake, and (B) subjects with lower circulating lycopene levels vs. subjects with higher circulating lycopene levels.*

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 [83–86]. They

**215**

*3.2.2 COPD*

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

mentation on exercise-induced asthma.

examined their pulmonary function at the end of the study [83–86]. 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 supple-

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].

pulmonary inflammation and lessen asthma manifestations.

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

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.

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

*Antioxidants - Benefits, Sources, Mechanisms of Action*

*Flow diagram of study selection according to the PRISMA guideline.*

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

*Forest plots for lung cancer risk in (A) subjects with lower lycopene intake vs. subjects with higher lycopene intake, and (B) subjects with lower circulating lycopene levels vs. subjects with higher circulating lycopene* 

Four RCTs supplemented asthma patients with lycopene or lycopene-enriched

foods to investigate the effect of dietary lycopene on asthma [83–86]. They

**214**

**Figure 2.**

**Figure 3.**

*levels.*

are unrelated to asthma development.

examined their pulmonary function at the end of the study [83–86]. 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.

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.

## *3.2.2 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.

#### *3.2.3 Lung cancer*

In total, 19 studies met our inclusion criteria and provided information on lycopene and lung cancer [32, 93–110]. Among them, there are 8 case–control studies that included 2,226 lung cancer patients [93, 95, 99, 100, 104, 105, 107, 110], 6 nested case–control studies that included 1,951 lung cancer cases [32, 94, 98, 102, 106, 108], and 5 prospective studies that included 218,251 subjects [96, 97, 101, 103, 109].

Among the studies that reported the association between lycopene intake and lung cancer risk, nine studies provided detailed study estimates [95, 96, 101–106, 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 (Chi2 ) 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

**217**

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

P = 0.0007), with the Chi2

investigation.

**4. Concluding remarks**

comparable between the cases and the controls [104].

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

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

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

In conclusion, we found consistent reports showing that dietary lycopene intake,

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

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.

p-value at 0.84, and the I2 at 0% (**Figure 3B**). Such data

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

*Antioxidants - Benefits, Sources, Mechanisms of Action*

COPD patients [75].

ment and prognosis.

subjects [96, 97, 101, 103, 109].

P < 0.0001). The p-value of the Chi-squared (Chi2

*3.2.3 Lung cancer*

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,

National Health and Nutrition Examination Survey (NHANES III), recruiting 1,492

In total, 19 studies met our inclusion criteria and provided information on lycopene and lung cancer [32, 93–110]. Among them, there are 8 case–control studies that included 2,226 lung cancer patients [93, 95, 99, 100, 104, 105, 107, 110], 6 nested case–control studies that included 1,951 lung cancer cases [32, 94, 98, 102, 106, 108], and 5 prospective studies that included 218,251

Among the studies that reported the association between lycopene intake and lung cancer risk, nine studies provided detailed study estimates [95, 96, 101–106, 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

study 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

) test is 0.52, and the between-

and 29 ACOS patients). The prospective study used the data from the Third

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 develop-

**216**

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 Chi2 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.

## **4. 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 [62–67].

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 [76–79], others found that asthma progression was not related to lycopene in the circulation [74, 75, 77, 80–82], suggesting that the association between asthma and lycopene concentrations in humans was not conclusive. We came across several epidemiological studies, including case– control, 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].

## **5. 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.

## **Acknowledgements**

The authors gratefully *acknowledge* the financial support of North Carolina State University. We also thank Baxter Miller for searching the research literature.

**219**

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

ROS reactive oxygen species

BALF bronchoalveolar lavage fluid EPO eosinophil peroxidase MMP-9 matrix metalloproteinase-9

TNF-α tumor necrosis factor-alpha

SAM senescence-accelerated mouse

MAPK mitogen-activated protein kinase

IPF idiopathic pulmonary fibrosis

LTO lycopene-enriched tomato oleserin NHBE normal human bronchial epithelial cells HMG-CoA 3-hydroxy-3-methylglutaryl–coenzyme A

FEV1 Forced expiratory volume in one second

NHANES III National Health and Nutrition Examination Survey

ACOS asthma-COPD overlap syndrome

BaP insulin-like growth factor binding protein-3, benzo[a]pyrene

NSCLC non-small cell lung cancer ROS reactive oxygen species

DMH dimethylhydrazine

RARβ retinoic acid receptor β GJC gap junction communication

FVC Forced vital capacity

ALT alanine aminotransferase

RCT randomized controlled trial

Cx43 connexin-43

RR relative ratio OR odds ratio HR hazard ratio

IFNγ interferon-gamma

ALI Acute lung injury LPS lipopolysaccharide MDA malondialdehyde MPO myeloperoxidase IL-6 interleukin-6 SG Sarcandra glabra

COPD Chronic obstructive pulmonary disease NNK nicotine-derived nitrosamine ketone

i.p. intraperitoneal OVA ovalbumin BW body weight

IL-4 interleukin-4 IL-5 interleukin-5

CAT catalase GSH glutathione IL-10 interleukin-10

OA oleic acid IL-1β interleukin-1β

BLM Bleomycin NO nitric oxide

#### **Abbreviations**


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

*Antioxidants - Benefits, Sources, Mechanisms of Action*

showing its chemoprevention capabilities [62–67].

**5. Future perspective**

**Acknowledgements**

**Abbreviations**

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

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 [76–79], others found that asthma progression was not related to lycopene in the circulation [74, 75, 77, 80–82], suggesting that the association between asthma and lycopene concentrations in humans was not conclusive. We came across several epidemiological studies, including case– control, 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].

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.

The authors gratefully *acknowledge* the financial support of North Carolina State

University. We also thank Baxter Miller for searching the research literature.

FRAP Ferric Reducing Antioxidant Power

SNPs single nucleotide polymorphisms

SLC27A6 solute carrier family 27 member 6

CD36 cluster of differentiation 36 molecule

ABCA1 ATP binding cassette subfamily a member 1

Gpx glutathione peroxidase GR glutathione reductase SOD superoxide dismutase

LPL lipoprotein lipase INSIG2 insulin-induced gene 2

APOB apolipoprotein B

LIPC lipase C

**218**


*Antioxidants - Benefits, Sources, Mechanisms of Action*

## **Author details**

Emilio Balbuena1,2,†, Junrui Cheng1,† and Abdulkerim Eroglu1,2\*

1 Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, USA

2 Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, USA

\*Address all correspondence to: aeroglu@ncsu.edu

† Balbuena and Cheng contributed equally to this work.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**221**

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

[1] Palozza, P., et al., *Tomato Lycopene and Inflammatory Cascade: Basic Interactions and Clinical Implications.* Curr Med Chem, 2010. **17**(23): p.

*carotenoid singlet oxygen quencher.* Arch Biochem Biophys, 1989. **274**(2):

[11] Stahl, W., et al., *Carotenoid mixtures protect multilamellar liposomes against oxidative damage: synergistic effects of lycopene and lutein.* FEBS Lett, 1998.

p. 532-538.

p. 205-213.

**427**(2): p. 305-308.

**29**(10): p. 1051-1055.

**56**(2 Pt 1): p. 35-51.

2019. **8**(6): p. 201.

**135**(8): p. 2042s–5s.

p. 65-77.

[12] Pennathur, S., et al., *Potent antioxidative activity of lycopene: A potential role in scavenging hypochlorous acid.* Free Radic Biol Med, 2010. **49**(2):

[13] Lee, A., D.I. Thurnham, and M. Chopra, *Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma.* Free Radic Biol Med, 2000.

[14] Subhash, K., C. Bose, and B.K. Agrawal, *Effect of short term supplementation of tomatoes on antioxidant enzymes and lipid* 

*peroxidation in type-II diabetes.* Indian J Clin Biochem, 2007. **22**(1): p. 95-98.

[15] Clinton, S.K., *Lycopene: chemistry, biology, and implications for human health and disease.* Nutr Rev, 1998.

[16] Soares, N.d.C.P., et al., *Comparative Analysis of Lycopene Content from Different Tomato-Based Food Products on the Cellular Activity of Prostate Cancer Cell Lines.* Foods (Basel, Switzerland),

[17] Porrini, M. and P. Riso, *What are typical lycopene intakes?* J Nutr, 2005.

[18] Kamiloglu, S., D. Boyacioglu, and E. Capanoglu, *The effect of food processing on bioavailability of tomato antioxidants.* Journal of Berry Research, 2013. **3**:

[2] Rao, A.V. and A. Ali, *Biologically Active Phytochemicals in Human Health: Lycopene.* International Journal of Food Properties, 2007. **10**(2): p. 279-288.

[3] Eroglu, A. and E.H. Harrison, *Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids.* J Lipid Res,

[4] Rowles, J.L., 3rd and J.W. Erdman, Jr., *Carotenoids and their role in cancer prevention.* Biochim Biophys Acta Mol Cell Biol Lipids, 2020. **1865**(11): p. 158613.

[5] Olson, J.A. and N.I. Krinsky, *Introduction: the colorful, fascinating world of the carotenoids: important physiologic modulators.* Faseb j, 1995.

[6] Palozza, P., et al., *Lycopene* 

*modulation of molecular targets affected by smoking exposure.* Curr Cancer Drug Targets, 2012. **12**(6): p. 640-657.

[7] Narayanasamy, S., et al., *Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.* J Lipid Res, 2017. **58**(5):

[8] Hu, K.Q., et al., *The biochemical characterization of ferret carotene-9′,10′ monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo.* J Biol Chem, 2006. **281**(28): p. 19327-19338.

[9] Kopec, R.E., et al., *Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma.* J Agric Food Chem, 2010. **58**(6): p. 3290-6.

[10] Di Mascio, P., S. Kaiser, and H. Sies, *Lycopene as the most efficient biological* 

**9**(15): p. 1547-1550.

p. 1021-1029.

2013. **54**(7): p. 1719-1730.

2547-2563.

**References**

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

## **References**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**220**

**Author details**

Kannapolis, NC, USA

Emilio Balbuena1,2,†, Junrui Cheng1,† and Abdulkerim Eroglu1,2\*

Life Sciences, North Carolina State University, Raleigh, NC, USA

\*Address all correspondence to: aeroglu@ncsu.edu

provided the original work is properly cited.

† Balbuena and Cheng contributed equally to this work.

1 Plants for Human Health Institute, North Carolina State University,

2 Department of Molecular and Structural Biochemistry, College of Agriculture and

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, [1] Palozza, P., et al., *Tomato Lycopene and Inflammatory Cascade: Basic Interactions and Clinical Implications.* Curr Med Chem, 2010. **17**(23): p. 2547-2563.

[2] Rao, A.V. and A. Ali, *Biologically Active Phytochemicals in Human Health: Lycopene.* International Journal of Food Properties, 2007. **10**(2): p. 279-288.

[3] Eroglu, A. and E.H. Harrison, *Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids.* J Lipid Res, 2013. **54**(7): p. 1719-1730.

[4] Rowles, J.L., 3rd and J.W. Erdman, Jr., *Carotenoids and their role in cancer prevention.* Biochim Biophys Acta Mol Cell Biol Lipids, 2020. **1865**(11): p. 158613.

[5] Olson, J.A. and N.I. Krinsky, *Introduction: the colorful, fascinating world of the carotenoids: important physiologic modulators.* Faseb j, 1995. **9**(15): p. 1547-1550.

[6] Palozza, P., et al., *Lycopene modulation of molecular targets affected by smoking exposure.* Curr Cancer Drug Targets, 2012. **12**(6): p. 640-657.

[7] Narayanasamy, S., et al., *Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.* J Lipid Res, 2017. **58**(5): p. 1021-1029.

[8] Hu, K.Q., et al., *The biochemical characterization of ferret carotene-9′,10′ monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo.* J Biol Chem, 2006. **281**(28): p. 19327-19338.

[9] Kopec, R.E., et al., *Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma.* J Agric Food Chem, 2010. **58**(6): p. 3290-6.

[10] Di Mascio, P., S. Kaiser, and H. Sies, *Lycopene as the most efficient biological* 

*carotenoid singlet oxygen quencher.* Arch Biochem Biophys, 1989. **274**(2): p. 532-538.

[11] Stahl, W., et al., *Carotenoid mixtures protect multilamellar liposomes against oxidative damage: synergistic effects of lycopene and lutein.* FEBS Lett, 1998. **427**(2): p. 305-308.

[12] Pennathur, S., et al., *Potent antioxidative activity of lycopene: A potential role in scavenging hypochlorous acid.* Free Radic Biol Med, 2010. **49**(2): p. 205-213.

[13] Lee, A., D.I. Thurnham, and M. Chopra, *Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma.* Free Radic Biol Med, 2000. **29**(10): p. 1051-1055.

[14] Subhash, K., C. Bose, and B.K. Agrawal, *Effect of short term supplementation of tomatoes on antioxidant enzymes and lipid peroxidation in type-II diabetes.* Indian J Clin Biochem, 2007. **22**(1): p. 95-98.

[15] Clinton, S.K., *Lycopene: chemistry, biology, and implications for human health and disease.* Nutr Rev, 1998. **56**(2 Pt 1): p. 35-51.

[16] Soares, N.d.C.P., et al., *Comparative Analysis of Lycopene Content from Different Tomato-Based Food Products on the Cellular Activity of Prostate Cancer Cell Lines.* Foods (Basel, Switzerland), 2019. **8**(6): p. 201.

[17] Porrini, M. and P. Riso, *What are typical lycopene intakes?* J Nutr, 2005. **135**(8): p. 2042s–5s.

[18] Kamiloglu, S., D. Boyacioglu, and E. Capanoglu, *The effect of food processing on bioavailability of tomato antioxidants.* Journal of Berry Research, 2013. **3**: p. 65-77.

[19] Başaran, N., M. Bacanlı, and A. Ahmet Başaran, *Chapter 28 - Lycopenes as Antioxidants in Gastrointestinal Diseases*, in *Gastrointestinal Tissue*, J. Gracia-Sancho and J. Salvadó, Editors. 2017, Academic Press. p. 355-362.

[20] Marković, K., M. Hruškar, and N. Vahčić, *Lycopene content of tomato products and their contribution to the lycopene intake of Croatians.* Nutrition Research, 2006. **26**(11): p. 556-560.

[21] Gärtner, C., W. Stahl, and H. Sies, *Lycopene is more bioavailable from tomato paste than from fresh tomatoes.* Am J Clin Nutr, 1997. **66**(1): p. 116-122.

[22] Danuta, G., et al., *Lycopene in tomatoes and tomato products.* Open Chemistry, 2020. **18**(1): p. 752-756.

[23] Unlu, N.Z., et al., *Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil.* J Nutr, 2005. **135**(3): p. 431-436.

[24] Borel, P., et al., *Lycopene bioavailability is associated with a combination of genetic variants.* Free Radical Biology and Medicine, 2015. **83**: p. 238-244.

[25] Moran, N.E., et al., *Single Nucleotide Polymorphisms in β-Carotene Oxygenase 1 are Associated with Plasma Lycopene Responses to a Tomato-Soy Juice Intervention in Men with Prostate Cancer.* The Journal of Nutrition, 2019. **149**(3): p. 381-397.

[26] Wang, X.-D., *Lycopene metabolism and its biological significance.* The American journal of clinical nutrition, 2012. **96**(5): p. 1214S–1222S.

[27] Moran, N.E., J.W. Erdman, Jr., and S.K. Clinton, *Complex interactions between dietary and genetic factors impact lycopene metabolism and distribution.* Archives of biochemistry and biophysics, 2013. **539**(2): p. 171-180.

[28] Story, E.N., et al., *An update on the health effects of tomato lycopene.* Annual review of food science and technology, 2010. **1**: p. 189-210.

[29] Tremblay, B.L., et al., *Genetic and Common Environmental Contributions to Familial Resemblances in Plasma Carotenoid Concentrations in Healthy Families.* Nutrients, 2018. **10**(8): p. 1002.

[30] Rust, P., P. Lehner, and I. Elmadfa, *Relationship between dietary intake, antioxidant status and smoking habits in female Austrian smokers.* Eur J Nutr, 2001. **40**(2): p. 78-83.

[31] Lagiou, P., et al., *Plasma carotenoid levels in relation to tobacco smoking and demographic factors.* Int J Vitam Nutr Res, 2003. **73**(3): p. 226-231.

[32] Yuan, J.M., et al., *Prediagnostic levels of serum beta-cryptoxanthin and retinol predict smoking-related lung cancer risk in Shanghai, China.* Cancer Epidemiol Biomarkers Prev, 2001. **10**(7): p. 767-773.

[33] Rao, A.V. and S. Agarwal, *Effect of diet and smoking on serum lycopene and lipid peroxidation.* Nutrition Research, 1998. **18**(4): p. 713-721.

[34] Petyaev, I.M., *Lycopene Deficiency in Ageing and Cardiovascular Disease.* Oxidative medicine and cellular longevity, 2016. **2016**: p. 3218605-3218605.

[35] Steck-Scott, S., et al., *Plasma and lung macrophage responsiveness to carotenoid supplementation and ozone exposure in humans.* Eur J Clin Nutr, 2004. **58**(12): p. 1571-1579.

[36] Holgate, S.T., *The airway epithelium is central to the pathogenesis of asthma.* Allergol Int, 2008. **57**(1): p. 1-10.

[37] Lee, C.M., et al., *Lycopene suppresses ovalbumin-induced airway inflammation in a murine model of asthma.* Biochem

**223**

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

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[47] Liu, T.Y. and S.B. Chen, *Sarcandra glabra combined with lycopene protect rats from lipopolysaccharide induced acute lung injury via reducing inflammatory response.* Biomed Pharmacother, 2016.

[48] Türkoğlu, S., et al., *Effects of lycopene on the model of oleic acidinduced acute lung injury.* Tuberk Toraks,

[49] Bastug, O., et al., *Effects of Lycopene in Hyperoxia-Induced Lung Injury in Newborn Rats.* Int J Vitam Nutr Res,

[50] Ballester, B., J. Milara, and J. Cortijo, *Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets.* Int J Mol Sci, 2019. **20**(3).

[51] Ley, B., H.R. Collard, and T.E. King, Jr., *Clinical course and prediction of survival in idiopathic pulmonary fibrosis.* Am J Respir Crit Care Med, 2011.

[52] Zhou, C., et al., *Lycopene from tomatoes partially alleviates the bleomycin-induced experimental pulmonary fibrosis in rats.* Nutr Res,

2012. **60**(2): p. 101-107.

2018. **88**(5-6): p. 270-280.

**183**(4): p. 431-440.

2008. **28**(2): p. 122-130.

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2005. **52**(4): p. 173-184.

p. 69-90.

[53] Muzandu, K., et al., *Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular* 

*modifications.* Toxicol Appl Pharmacol,

[54] Muzandu, K., et al., *Lycopene and beta-carotene ameliorate catechol estrogenmediated DNA damage.* Jpn J Vet Res,

[55] Jemal, A., et al., *Global cancer statistics.* CA Cancer J Clin, 2011. **61**(2):

**20**(1): p. 455-462.

**84**: p. 34-41.

[38] Hazlewood, L.C., et al., *Dietary lycopene supplementation suppresses Th2 responses and lung eosinophilia in a mouse model of allergic asthma.* J Nutr Biochem, 2011. **22**(1): p. 95-100.

[39] Barnes, P.J., et al., *Chronic obstructive pulmonary disease.* Nat Rev Dis Primers,

[40] Vestbo, J., et al., *Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.* Am J Respir Crit Care Med,

[41] Mustra Rakic, J., et al., *Lycopene Inhibits Smoke-Induced Chronic Obstructive Pulmonary Disease and Lung Carcinogenesis by Modulating Reverse Cholesterol Transport in Ferrets.* Cancer Prev Res (Phila), 2019. **12**(7): p.

[42] Campos, K.K.D., et al., *Lycopene mitigates pulmonary emphysema induced by cigarette smoke in a murine model.* J Nutr Biochem, 2019. **65**: p. 93-100.

[43] Campos, K.K.D., et al., *The antioxidant and anti-inflammatory properties of lycopene in mice lungs exposed to cigarette smoke.* J Nutr Biochem, 2017. **48**: p. 9-20.

[44] Kasagi, S., et al., *Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke.* Am J Physiol Lung Cell Mol Physiol, 2006. **290**(2): p. L396–L404.

[45] Johnson, E.R. and M.A. Matthay, *Acute lung injury: epidemiology,* 

*pathogenesis, and treatment.* J Aerosol Med Pulm Drug Deliv, 2010. **23**(4): p. 243-252.

[46] Li, W.W., et al., *Synergistic protection* 

*of matrine and lycopene against* 

p. 248-252.

2015. **1**: p. 15076.

2013. **187**(4): p. 347-365.

421-432.

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

Biophys Res Commun, 2008. **374**(2): p. 248-252.

*Antioxidants - Benefits, Sources, Mechanisms of Action*

[28] Story, E.N., et al., *An update on the health effects of tomato lycopene.* Annual review of food science and technology,

[29] Tremblay, B.L., et al., *Genetic and Common Environmental Contributions to Familial Resemblances in Plasma Carotenoid Concentrations in Healthy Families.* Nutrients, 2018. **10**(8): p. 1002.

[30] Rust, P., P. Lehner, and I. Elmadfa, *Relationship between dietary intake, antioxidant status and smoking habits in female Austrian smokers.* Eur J Nutr,

[31] Lagiou, P., et al., *Plasma carotenoid levels in relation to tobacco smoking and demographic factors.* Int J Vitam Nutr

[32] Yuan, J.M., et al., *Prediagnostic levels of serum beta-cryptoxanthin and retinol predict smoking-related lung cancer risk in Shanghai, China.* Cancer Epidemiol Biomarkers Prev, 2001. **10**(7): p.

[33] Rao, A.V. and S. Agarwal, *Effect of diet and smoking on serum lycopene and lipid peroxidation.* Nutrition Research,

[34] Petyaev, I.M., *Lycopene Deficiency* 

2010. **1**: p. 189-210.

2001. **40**(2): p. 78-83.

767-773.

Res, 2003. **73**(3): p. 226-231.

1998. **18**(4): p. 713-721.

3218605-3218605.

*in Ageing and Cardiovascular Disease.* Oxidative medicine and cellular longevity, 2016. **2016**: p.

[35] Steck-Scott, S., et al., *Plasma and lung macrophage responsiveness to carotenoid supplementation and ozone exposure in humans.* Eur J Clin Nutr,

[36] Holgate, S.T., *The airway epithelium is central to the pathogenesis of asthma.* Allergol Int, 2008. **57**(1): p. 1-10.

[37] Lee, C.M., et al., *Lycopene suppresses ovalbumin-induced airway inflammation in a murine model of asthma.* Biochem

2004. **58**(12): p. 1571-1579.

[19] Başaran, N., M. Bacanlı, and A. Ahmet Başaran, *Chapter 28 - Lycopenes as Antioxidants in Gastrointestinal Diseases*, in *Gastrointestinal Tissue*, J. Gracia-Sancho and J. Salvadó, Editors. 2017, Academic Press. p. 355-362.

[20] Marković, K., M. Hruškar, and N. Vahčić, *Lycopene content of tomato products and their contribution to the lycopene intake of Croatians.* Nutrition Research, 2006. **26**(11): p. 556-560.

[21] Gärtner, C., W. Stahl, and H. Sies, *Lycopene is more bioavailable from tomato paste than from fresh tomatoes.* Am J Clin

Nutr, 1997. **66**(1): p. 116-122.

[22] Danuta, G., et al., *Lycopene in tomatoes and tomato products.* Open Chemistry, 2020. **18**(1): p. 752-756.

[23] Unlu, N.Z., et al., *Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil.* J Nutr, 2005.

[24] Borel, P., et al., *Lycopene bioavailability is associated with a combination of genetic variants.* Free Radical Biology and Medicine, 2015. **83**:

[25] Moran, N.E., et al., *Single Nucleotide Polymorphisms in β-Carotene Oxygenase 1 are Associated with Plasma Lycopene Responses to a Tomato-Soy Juice* 

*Intervention in Men with Prostate Cancer.* The Journal of Nutrition, 2019. **149**(3):

[26] Wang, X.-D., *Lycopene metabolism and its biological significance.* The American journal of clinical nutrition,

2012. **96**(5): p. 1214S–1222S.

[27] Moran, N.E., J.W. Erdman, Jr., and S.K. Clinton, *Complex interactions between dietary and genetic factors impact lycopene metabolism and distribution.* Archives of biochemistry and biophysics, 2013. **539**(2): p. 171-180.

**135**(3): p. 431-436.

p. 238-244.

p. 381-397.

**222**

[38] Hazlewood, L.C., et al., *Dietary lycopene supplementation suppresses Th2 responses and lung eosinophilia in a mouse model of allergic asthma.* J Nutr Biochem, 2011. **22**(1): p. 95-100.

[39] Barnes, P.J., et al., *Chronic obstructive pulmonary disease.* Nat Rev Dis Primers, 2015. **1**: p. 15076.

[40] Vestbo, J., et al., *Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.* Am J Respir Crit Care Med, 2013. **187**(4): p. 347-365.

[41] Mustra Rakic, J., et al., *Lycopene Inhibits Smoke-Induced Chronic Obstructive Pulmonary Disease and Lung Carcinogenesis by Modulating Reverse Cholesterol Transport in Ferrets.* Cancer Prev Res (Phila), 2019. **12**(7): p. 421-432.

[42] Campos, K.K.D., et al., *Lycopene mitigates pulmonary emphysema induced by cigarette smoke in a murine model.* J Nutr Biochem, 2019. **65**: p. 93-100.

[43] Campos, K.K.D., et al., *The antioxidant and anti-inflammatory properties of lycopene in mice lungs exposed to cigarette smoke.* J Nutr Biochem, 2017. **48**: p. 9-20.

[44] Kasagi, S., et al., *Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke.* Am J Physiol Lung Cell Mol Physiol, 2006. **290**(2): p. L396–L404.

[45] Johnson, E.R. and M.A. Matthay, *Acute lung injury: epidemiology, pathogenesis, and treatment.* J Aerosol Med Pulm Drug Deliv, 2010. **23**(4): p. 243-252.

[46] Li, W.W., et al., *Synergistic protection of matrine and lycopene against* 

*lipopolysaccharide-induced acute lung injury in mice.* Mol Med Rep, 2019. **20**(1): p. 455-462.

[47] Liu, T.Y. and S.B. Chen, *Sarcandra glabra combined with lycopene protect rats from lipopolysaccharide induced acute lung injury via reducing inflammatory response.* Biomed Pharmacother, 2016. **84**: p. 34-41.

[48] Türkoğlu, S., et al., *Effects of lycopene on the model of oleic acidinduced acute lung injury.* Tuberk Toraks, 2012. **60**(2): p. 101-107.

[49] Bastug, O., et al., *Effects of Lycopene in Hyperoxia-Induced Lung Injury in Newborn Rats.* Int J Vitam Nutr Res, 2018. **88**(5-6): p. 270-280.

[50] Ballester, B., J. Milara, and J. Cortijo, *Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets.* Int J Mol Sci, 2019. **20**(3).

[51] Ley, B., H.R. Collard, and T.E. King, Jr., *Clinical course and prediction of survival in idiopathic pulmonary fibrosis.* Am J Respir Crit Care Med, 2011. **183**(4): p. 431-440.

[52] Zhou, C., et al., *Lycopene from tomatoes partially alleviates the bleomycin-induced experimental pulmonary fibrosis in rats.* Nutr Res, 2008. **28**(2): p. 122-130.

[53] Muzandu, K., et al., *Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular modifications.* Toxicol Appl Pharmacol, 2006. **215**(3): p. 330-340.

[54] Muzandu, K., et al., *Lycopene and beta-carotene ameliorate catechol estrogenmediated DNA damage.* Jpn J Vet Res, 2005. **52**(4): p. 173-184.

[55] Jemal, A., et al., *Global cancer statistics.* CA Cancer J Clin, 2011. **61**(2): p. 69-90.

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[88] Beck, K.C., M.J. Joyner, and P.D. Scanlon, *Exercise-Induced asthma: diagnosis, treatment, and regulatory issues.* Exerc Sport Sci Rev, 2002. **30**(1): p. 1-3.

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[93] Asbaghi, S., et al., *Dietary Intake and Serum Level of Carotenoids in Lung Cancer Patients: A Case-Control Study.* Nutr Cancer, 2015. **67**(6): p. 893-898.

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**227**

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

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Prev, 2003. **12**(9): p. 890-898.

[110] Bakker Schut, T.C., et al.,

**74**(1): p. 20-25.

*Intracellular carotenoid levels measured by Raman microspectroscopy: comparison of lymphocytes from lung cancer patients and healthy individuals.* Int J Cancer, 1997.

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

*Antioxidants - Benefits, Sources, Mechanisms of Action*

*advanced stage lung cancer patients.* Nutrition, 2011. **27**(11-12):

[100] Le Marchand, L., et al., *Vegetable consumption and lung cancer risk: a population-based case-control study in Hawaii.* J Natl Cancer Inst, 1989. **81**(15):

[101] Michaud, D.S., et al., *Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts.* Am J Clin Nutr, 2000. **72**(4): p. 990-997.

[102] Rohan, T.E., et al., *A cohort study of dietary carotenoids and lung cancer risk in women (Canada).* Cancer Causes

[103] Satia, J.A., et al., *Long-term use of beta-carotene, retinol, lycopene, and lutein supplements and lung cancer risk: results from the VITamins And Lifestyle (VITAL) study.* Am J Epidemiol, 2009. **169**(7): p.

Control, 2002. **13**(3): p. 231-237.

[104] Shareck, M., et al., *Inverse Association between Dietary Intake of Selected Carotenoids and Vitamin C and Risk of Lung Cancer.* Front Oncol, 2017.

[105] Stefani, E.D., et al., *Dietary antioxidants and lung cancer risk: a casecontrol study in Uruguay.* Nutr Cancer,

[106] Steinmetz, K.A., J.D. Potter, and A.R. Folsom, *Vegetables, fruit, and lung cancer in the Iowa Women's Health Study.* Cancer Res, 1993. **53**(3): p. 536-543.

*inflammation on measures of antioxidant status in patients with non-small cell lung cancer.* Am J Clin Nutr, 1997. **66**(5): p.

[108] Voorrips, L.E., et al., *A prospective cohort study on antioxidant and folate intake and male lung cancer risk.* Cancer Epidemiol Biomarkers Prev, 2000. **9**(4):

[107] Talwar, D., et al., *Effect of* 

1999. **34**(1): p. 100-110.

p. 1156-1160.

p. 1158-1164.

815-828.

**7**: p. 23.

1283-5.

p. 357-365.

[91] Cukic, V., et al., *Asthma and Chronic Obstructive Pulmonary Disease (COPD) - Differences and Similarities.* Materia socio-medica, 2012. **24**(2): p. 100-105.

[92] Kentson, M., et al., *Oxidant status, iron homeostasis, and carotenoid levels of COPD patients with advanced disease and LTOT.* Eur Clin Respir J, 2018. **5**(1): p.

[93] Asbaghi, S., et al., *Dietary Intake and Serum Level of Carotenoids in Lung Cancer Patients: A Case-Control Study.* Nutr Cancer, 2015. **67**(6): p. 893-898.

[94] Comstock, G.W., et al., *The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acids, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.* Am J Epidemiol, 2008. **168**(7):

[95] Garcia-Closas, R., et al., *Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain.* Nutr Cancer, 1998. **32**(3): p.

[96] Holick, C.N., et al., *Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study.* Am J Epidemiol, 2002. **156**(6):

[97] Ito, Y., et al., *Cancer mortality and serum levels of carotenoids, retinol, and tocopherol: a population-based follow-up study of inhabitants of a rural area of Japan.* Asian Pac J Cancer Prev, 2005.

[98] Ito, Y., et al., *Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study.* J Epidemiol, 2005. **15 Suppl** 

[99] Klarod, K., et al., *Serum antioxidant levels and nutritional status in early and* 

1447221.

p. 831-840.

154-158.

p. 536-547.

**6**(1): p. 10-15.

**2**: p. S140–S149.

**226**

[109] Yuan, J.M., et al., *Dietary cryptoxanthin and reduced risk of lung cancer: the Singapore Chinese Health Study.* Cancer Epidemiol Biomarkers Prev, 2003. **12**(9): p. 890-898.

[110] Bakker Schut, T.C., et al., *Intracellular carotenoid levels measured by Raman microspectroscopy: comparison of lymphocytes from lung cancer patients and healthy individuals.* Int J Cancer, 1997. **74**(1): p. 20-25.

**229**

**Chapter 12**

**Abstract**

Nutrients

of diabetic eye disease.

diabetic retinopathy

**1. Introduction**

significant global health problem [2].

*Drake W. Lem, Dennis L. Gierhart* 

*and Pinakin Gunvant Davey*

Management of Diabetic Eye

Disease Using Carotenoids and

Diabetic retinopathy is the leading cause of blindness and visual disability globally among working-age adults. Until recently, diabetic eye disease is primarily regarded by its microvasculature complications largely characterized by progressive retinopathy and macular edema. However, a growing body of evidence suggests that hyperglycemia-induced oxidative stress and inflammation play an integral role in the early pathogenesis of diabetic retinopathy by potentiating retinal neurodegeneration. The onset of type 2 diabetes mellitus starts with insulin resistance leading to insulin deficiency, hyperglycemia, and dyslipidemia. Which in turn enhances the pro-oxidant and pro-inflammatory pathways. Additionally, various poor dietary behaviors along with obesity worsen physiological state in diabetics. However, decreased levels and depletion of the endogenous antioxidant defense system in the retina can be sufficiently augmented via carotenoid vitamin therapy. Therefore, dietary supplementation of antioxidant micronutrients particularly macular

carotenoids lutein, zeaxanthin and *meso*-zeaxanthin that promote retinal health and optimal visual performance, may serve as an adjunctive therapy in the management

**Keywords:** carotenoids, macular pigment, macular pigment optical density, MPOD,

The prevalence of diabetes is endemic in the United States and developed countries. According to the 2018 reports it is estimated that the United States has more than 31 million adults diagnosed with diabetes [1]. Diabetes prevalence remains underestimated with approximately one in four individuals that have diabetes are undiagnosed [1]. There are various forms of diabetes and individuals with Type 2 diabetes (T2DM) account for 90–95% of all cases of diabetes within the US [1]. The incidence of diabetes is also likely to increase with 88 million individuals are diagnosed to be pre-diabetic who have potential ongoing subclinical damage [1]. The prevalence of diabetes mellitus in the US is predicted to reach 36 million by the year 2045 and will continue to pose a

lutein, zeaxanthin and meso-zeaxanthin, diabetes, diabetic eye disease,

## **Chapter 12**
