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Serkan Kapancik✶, Atteneri López Arencibia, and Burak Tuzun
Chapter 10 Medicinal and aromatic plants used in respiratory diseases
Abstract: In ancient times, people sought remedies in plants found in nature to treat
their illnesses. The use of medicinal plants by people is quite old. The information ob tained about these plants is based on the experiences that emerged after their use, and as a result of medical developments, the therapeutic effectiveness of many plants on diseases has been proven by scientific studies today. A wide variety of medicinal and aromatic plants are frequently used in the treatment of many diseases such as cancer, immune system diseases, endocrine diseases, cardiovascular diseases, diges tive disorders, kidney and liver diseases, central nervous system diseases, gastrointes­tinal diseases, inflammatory diseases, skin diseases, and respiratory diseases. One of the diseases for which medicinal and aromatic plants are used for treatment purposes is respiratory system diseases. Mortality rates due to respiratory diseases are quite high worldwide. In order to reduce the mortality rates caused by respiratory diseases, alternative treatment methods that will contribute to the treatment of respiratory dis eases are needed. For this reason, studies on the role of medicinal and aromatic plants in the treatment of respiratory diseases are increasing day by day. In this part of the book, we will discuss the roles of medicinal and aromatic plants in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pneumonia, and lung cancer in the light of scientific research.
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Keywords: medicinal and aromatic plants, chronic obstructive pulmonary disease, asthma, pneumonia, lung cancer

10.1 Introduction

Medicinal and aromatic plants have great therapeutic importance worldwide through the bioactive molecules they contain. In ancient times, people sought remedies in plants in nature in order to treat their diseases. Although medicinal plants’ use by
Corresponding author: Dr. Serkan Kapancik, Department of Biochemistry, School of Medicine, Sivas Cumhuriyet University, Sivas, Turkey, e-mail: serkankapancik@gmail.com, https://orcid.org/0000-0003-3019-4275
Atteneri López Arencibia, Universidad De La Laguna, La Laguna, Tenerife, Islas Canarias 38203, Spain Burak Tuzun, Plant and Animal Production Department, Technical Sciences Vocational School of Sivas,
Sivas Cumhuriyet University, Sivas, Turkey
Figure 10.1: Obtaining plant extract through extraction of plants (created via BioRender.com).
364 Serkan Kapancik, Atteneri López Arencibia, and Burak Tuzun
people is quite old, the information obtained about these plants was also based on the experience that emerged after their use. Through experience, it began to be revealed which plants could be used in the treatment of which disease. With the development of pharmacology in recent years, the use of medicinal plants for therapeutic purposes has increased due to the decrease in the therapeutic capabilities of synthetic drugs synthesized in laboratories. The biggest reason for this is the low side effects of medic­inal plants compared to synthetic drugs produced pharmacologically. Medicinal and aromatic plants, which have a wide variety, are frequently used in the treatment of many diseases such as cancer, immune diseases, endocrine diseases, cardiovascular diseases, digestive disorders, kidney and liver diseases, central nervous system dis­eases, gastrointestinal diseases, and inflammatory diseases [1, 2]. Respiratory system diseases, one of the diseases in which medicinal and aromatic plants are used for treatment, refer to the group of diseases that occur in the organs and tissues related to respiration, which prevent individuals from maintaining their respiratory func­tions in a healthy way. In order to be used for therapeutic purposes, medicinal and aromatic plants are subjected to the extraction method as shown in Figure 10.1, and their extracts are obtained in this way.
Mortality rates from respiratory diseases continue to occur at high rates despite ad­vances in medicine. The rate of contracting chronic obstructive pulmonary disease (COPD), which is in the group of respiratory diseases, is quite high. This number has reached 65 million. Mortality rates from COPD rank fourth when compared to mortal­ity rates from other diseases worldwide. Asthma is a respiratory disease that affects
Chapter 10 Medicinal and aromatic plants used in respiratory diseases 365
approximately 14% of children in the world and is also frequently encountered in adults. Pneumonia is especially fatal in children under the age of 5 and causes the death of millions of people. Lung cancer is an important respiratory disease that causes the death of 1.4 million people every year and has higher mortality rates com­pared to other types of cancer. Tuberculosis is another respiratory disease that causes high mortality. Approximately 1.4 million people die each year due to tuberculosis. In general, approximately 4 million people die from chronic respiratory diseases each year [1, 3]. In this chapter, we will discuss the therapeutic effects of medicinal and aromatic plants for each respiratory disease.

10.2 COPD

COPD is a disease based on tissue damage caused by oxidative stress and oxidant ac­cumulation caused by inflammation. Since the treatments associated with this disease are not fully sufficient, in a study investigating whether Ocimum sanctum leaf extract has a therapeutic role in COPD, it was observed that in a model of COPD formation in mice exposed to cigarette smoke, as in Figure 10.2, the administration of the plant ex­tract increased antioxidant capacity and decreased oxidant capacity. This resulted in a decrease in inflammation, and in this respect, Ocimum sanctum leaf extract exhib­ited a protective effect against COPD formation. Due to these effects, it has been re­ported that Ocimum sanctum leaf extract can be used in COPD [4].
Again, the effects of the alcohol extracts of the medicinal plants Mikania glomer- ata Spreng, Plantago major, Equisetum arvense, and Arctium lappa on the disease were investigated in a COPD rat model created by exposure to cigarette smoke. When the animals were exposed to the process in Figure 10.2 for 2 months and the plant extracts obtained during this period were given to the rats, it was shown that the mac­rophages and mast cells in the lungs of the rats were suppressed compared to the group that was not given the plant extract. This situation indicates that the inflamma­tion levels of the animals that were given the plant extracts decreased, and it has been reported that these plants may have a therapeutic and protective role for COPD because the plant extract application prevents inflammation through the decrease in inflammatory mediator levels [5]. In the COPD mouse model where Epilobium pyrri- cholophum extracts were applied, it was shown that clinical symptoms were sup­pressed as a result of the inhibition of cell aggregation with inflammatory properties. Although it is known that Epilobium pyrricholophum extracts mediate a decrease in the levels of radical, especially in immune cells, and reduce myeloperoxidase and cy­tokine release, it has also been reported that these plant extracts have an effect on reducing inflammation by suppressing NFκB expression in the COPD mouse model. In this respect, it has been suggested that the Epilobium pyrricholophum plant may con­tribute to the treatment of COPD by suppressing both the immune and the inflamma-
Figure 10.2: COPD mouse model with cigarette smoke exposure (created via BioRender.com).
Figure 10.3: COPD mouse model induced with lipopolysaccharide or elastase (created via BioRender.
com).
366 Serkan Kapancik, Atteneri López Arencibia, and Burak Tuzun
tion genes [6]. The effect of ethanol extracts obtained from the Alisma orientale Juzep­zuk on the COPD mouse model was also investigated in another study. In this study, a mouse COPD model was created as in Figure 10.3 after the application of lipopolysac­charide as a spray, in addition to the intratracheal application of elastase to the mice.
Chapter 10 Medicinal and aromatic plants used in respiratory diseases 367
Then, by looking at the levels of genes and proteins related to inflammation, it was in­vestigated whether ethanol extracts obtained from the tuber of Alisma orientale Juzep­zuk had a therapeutic role on COPD disease. It was determined that inflammation in the lungs decreased, following the application of the plant extract in the COPD model. In ad­dition, it was observed that the levels of proinflammatory cytokines such as TNF-α, TGF­β, and IL-6, which are related to inflammation, decreased. Based on these results, it was reported that the Alisma orientale Juzepzuk reduces the pathological aspects of the dis­ease by suppressing lung inflammation in COPD [7]. Lonicera japonica flower has antiox­idant properties. It is mostly used in East Asia for its therapeutic properties. Research has also been conducted on the effectiveness of Lonicera japonica flower in COPD. For this study, a COPD model was developed in mice. For this model, after applying lipopoly­saccharide and smoking solution to mice, it was determined that the expression of IL-6 and TNF-α, which are genes related to inflammation, decreased in animals exposed to Lonicera japonica flower treatment. However, the application of Lonicera japonica flower microparticles also caused serious decreases in inflammatory-related cells. In ad­dition, it was reported that the treatment of this medicinal plant mediated a decrease in the expression of Caspase3, which may play a role in apoptosis that may be induced as a result of the increase in oxidant amounts in the lungs of COPD model mice. As a result, it has been suggested that the inhalation of plant flower microparticles may be a promis­ing treatment strategy for COPD treatment [8]. The stem, leaves and root of the Celastrus
orbiculatus Thunb. plant are used to contribute to the treatment of diseases. Therefore, Celastrus orbiculatus Thunb. is also included in the class of medicinal plants. The thera-
peutic effects of Celastrus orbiculatus Thunb., its in vitro effects on COPD, have also been investigated. For this purpose, A549 lung cancer cell lines were exposed to cigarette smoke extract to create an inflammatory cell model, and then when the stem, leaves, and root extracts of the plant were applied to A549 cells, it was shown that the levels of proinflammatory factors decreased in a dose-dependent manner. However, it was em­phasized that the stem part of the plant may be effective for COPD compared to the root and leaf parts [9]. It was aimed to scientifically reveal its role in COPD by examining the effect of Pseudognaphalium affine (D.Don) Anderb. which is used by humans for cough, COPD, and asthma, on an in vivo COPD mouse model. In this study, it was observed that Pseudognaphalium affine (D.Don) Anderb. extract application in a COPD mouse model suppressed damage in the lungs of animals. Pseudognaphalium affine (D.Don) Anderb. achieved this by reducing the levels of proinflammatory cytokines that cause the emer­gence of inflammatory effect. In particular, application of the plant’s extract has been the most important mechanism in preventing inflammation through suppression of pro­tein levels as a result of suppressing the expression of NF-κB. Based on this, the extract of Pseudognaphalium affine (D.Don) Anderb. has been reported to be effective against COPD due to the inhibition of this pathway by suppressing proinflammatory cytokines and causing a decrease in NF-κB levels [10]. Isodon suzhouensis is a plant that is both edible and used for medical treatment. Due to its inflammation-reducing properties, the effectiveness of plant extracts was investigated in mice with COPD models in order to
368 Serkan Kapancik, Atteneri López Arencibia, and Burak Tuzun
determine whether it has therapeutic properties. The therapeutic activities of Isodon suz­houensis and its active component, glycocalycin A, were investigated in animals, with
COPD models. It was determined that Isodon suzhouensis extracts improved lung func­tions in mice. However, it was observed that they suppressed inflammation by reducing IL-1β and TNF-α levels. It was reported that Isodon suzhouensis extracts prevented the development of COPD by suppressing inflammation, prevented apoptosis of cells in lung tissue, and reduced the expression levels of proteins in the JAKs/STATs pathway. Glyoca­lysin A has been shown to suppress proinflammatory factors in a COPD mouse model and to have an ameliorating effect on COPD by inhibiting the JAKs/STATs pathway [11]. It is known that Azadirachta indica A. Juss. leaf has antioxidant effects and anti­inflammatory properties. Due to these properties of this medicinal plant, its effect on COPD has also been investigated in a study. It has been determined that the extract of plant leaf reduces the levels of reactive oxygen species and the number of inflammatory cells in bronchoalveolar lavage fluid against inflammation caused by cigarette smoke and lipopolysaccharide. In addition, it has been determined that the levels of proinflam­matory IL-6 and TNF-α in bronchoalveolar lavage fluid are reduced by the plant extract. It has been reported that plant leaf extract reduces the inducible nitrite oxide synthase expression in lung tissue in a COPD mouse model, prevents ERK and JNK activation, and suppresses phosphorylation of TNF-α, and has the potential to be used in the treatment of COPD due to these findings [12]. Thymus vulgaris L. is known for its therapeutic prop­erties for respiratory diseases. It has been suggested that the application of Thymus vul- garis L., known as a traditional medicinal plant, may have therapeutic effects for COPD by reducing NF-κB levels, IL-1beta, and IL-8 levels. In addition, it has been shown that the mucociliary-beating frequency, which is impaired in COPD, can be increased by me­diating an induce, increasing the Ca2 + and cAMP levels with the application of Thymus
vulgaris L. extract, and thus can be used as a support for COPD treatment [13]. Myrciaria cauliflora is an edible fruit and is also used as a treatment for asthma. It has been sug-
gested that Myrciaria cauliflora can also be used as a treatment for COPD due to its anti­inflammatory effects [14]. Lilium longiflorum Thunb plant is also one of the medicinal plants known to have anti-inflammatory properties. In a COPD mouse model created with porcine pancreas elastase and cigarette smoke extract, oral administration of fer­mented lilium longiflorum Thunb bulb extract has been shown to suppress inflammation by suppressing the infiltration of immune cells and the producing inflammatory media­tors, thus preventing lung damage. In addition, fermented Lilium longiflorum Thunb bulb extract has been shown to mediate a decrease in the levels of IL-8 and IL-6, which are proinflammatory factors that are increased, in levels with cigarette smoke extract and lipopolysaccharide in the epithelial cell line H292 cells. It has been reported that fer­mented Lilium longiflorum Thunb bulb extract is effective in preventing and slowing down inflammation in an animal model of COPD [15]. Baru nut is a species that contains high antioxidants and phenols with therapeutic properties. It has been reported that the baru nut ethanol extract reduces reactive oxygen species in NCI-H441 and A549 lung epi­thelial cells and contributes to wound healing. Therefore, it has been mentioned that
Figure 10.4: COPD cell line model induced with lipopolysaccharide (created via BioRender.com).
Chapter 10 Medicinal and aromatic plants used in respiratory diseases 369
baru nut may be a beneficial species for diseases such as COPD, which are based on oxi­dative stress [16]. Scientific studies have shown that the Zataria multiflora plant has a high antioxidant content and can contribute to the treatment of respiratory diseases due to its inflammation-suppressing effects. It has been shown that COPD patients who were given the extract of the Zataria multiflora plant had inflammation-reducing effects and that the plant extract had an effect on the treatment of COPD [17]. Anti-inflammatory drugs are used in COPD patients. The effect of these drugs is based on the principle of inhibiting inflammation by inhibiting cyclooxygenase-2 (COX-2). Thus, the increase in in­flammation in the lungs of COPD patients can be prevented. In the study investigating the relationship between COX-2 and the extracts obtained from kersen leaf (Muntingia calabura) and Legetan warak (Adenostemma lavenia), it was shown that these plant ex­tracts inhibit COX-2 and thus suppress inflammation [18]. It has been reported that COPD patients who were given capsules containing the hydroalcoholic extract of rosemary had healing effects and showed an increase in cognitive functions [19]. In a study investigat­ing the effects of Angelicae dahuricae Radix on a mouse COPD model created with lipo­polysaccharide and cigarette smoke extract, it was reported that the plant extract caused suppression of COPD disease. In this study, it was suggested that Angelicae dahuricae Radix extract suppressed the level of inflammatory cells that increased in the bronchoal­veolar lavage fluid after application to animals, with a COPD model, thus causing an in­hibitory effect on COPD [20]. The therapeutic effects of the Siraitia grosvenorii plant were investigated in a scientific study in the COPD mouse model created with cigarette smoke extract and lipopolysaccharide and in BEAS-2B cells to which lipopolysaccharide was applied, as in Figure 10.4.
In this study, it was shown that Siraitia grosvenorii extract mediates the preservation of viability in BEAS-2B cells treated with lipopolysaccharide and reduces the expres­sion and levels of inflammation-related cytokines in these cells. An increase in the in­filtration of immune cells into the respiratory tract of animal with a COPD model was observed, and it was shown that Siraitia grosvenorii extract suppressed this condition. In addition, plant extracts mediated a decrease in cytokine release in the bronchoal­veolar fluid of mice, with a COPD model. Using these findings, it was reported that
370 Serkan Kapancik, Atteneri López Arencibia, and Burak Tuzun
Siraitia grosvenorii has an anti-inflammatory activity and that it could be a potential herbal medicine for the treatment of COPD due to these properties [21].

10.3 Asthma

The effectiveness of hexane, methanol, and ethyl acetate extracts of Asystasia gangetica T. Adams leaf in the treatment of asthma was investigated through a study. Since Asysta- sia gangetica T. Adams leaf is known to be used for asthma among the public, this study revealed the scientific role of the plant in the treatment of the disease. It was determined that the plant extracts prevented the contraction induced by using spasmogens. In addi­tion, the extracts also mediated the relaxation of tracheal strips contracted using hista­mine. Among the extracts of Asystasia gangetica T. Adams leaf, methanol extract has the highest anti-inflammatory effects on mice. Based on the evidences obtained from study, it has been stated that Asystasia gangetica T. Adams leaf may be effective in asthma [22]. In the ovalbumin-induced asthma mouse model, it has been reported that Ocimum basili- cum leaves have a therapeutic effect. In this study, the application of plant extracts in asthma model caused inhibition in PLA2, TP, IgE, and IL-4 levels, while there was an in­crease in the IFN-γ/IL-4 ratio. The fact that Ocimum basilicum leaves mediate the improve­ment in inflammatory and immunological factors is important in terms of the use of this plant in asthma and its therapeutic potential in asthma disease [23]. Inula racemosa Hook. F. is a plant, and its roots are often used for antiseptic purposes, as an anti­inflammatory, digestive, and antipyretic drug, and have important therapeutic effects. Inula racemosa Hook. F. root extracts have been investigated in vivo and in vitro for their possible therapeutic roles in asthma. It has been determined that the root of the plant, especially its petroleum ether extracts, has an antigonist effect on histamine­induced contractions. Based on the immunological, biochemical, and physical findings of the study, it has been emphasized that the plant may have a potential therapeutic role in asthma [24]. Chronic exposure of the airways, where breathing takes place to inflamma­tion, mediates the emergence of asthma. The possible role of the medicinal plant L. aspera in asthma has also been investigated and it has been determined that dried whole plant extracts have therapeutic properties for asthma. Methanol extracts were ex­tracted from dried whole plant parts of L. aspera and these methanol extracts were used in the study. It has been shown that L. aspera methanol extract may have an important therapeutic effect for asthma due to its bronchodilator, inflammation suppressor, antihis­tamine, mast cell stabilizing, and anticholinergic activity in asthma models [25]. It has been reported that the methanol extract of Moringa oleifera Lam. leaves prevents inflam­mation in the respiratory tract, causes bronchoconstriction and may be useful against asthma due to these medicinal effects. In order to demonstrate the therapeutic effects of Moringa oleifera Lam. leaf methanol extract against asthma, an ovalbumin-induced asthma model was used in guinea pigs. Application of plant leaf methanol extracts to
Chapter 10 Medicinal and aromatic plants used in respiratory diseases 371
asthma model animals caused improvement in the lung functions of these animals [26]. In the study investigating the effects of water, ethanol, and petroleum ether extracts of Solanum xanthocarpum flowers on asthma in vivo and in vitro, it was stated that the eth­anol extract of Solanum xanthocarpum flowers may have a potential role in the treatment of asthma because it provides mast cell stabilization, produces antihistaminic effects, and produces effects in reducing capillary permeability [27]. It is known that the fruit of the Solanum nigrum Linn plant is used, especially for asthma, among the public. Therefore, in the study conducted to reveal the role of the fruit of the Solanum nigrum Linn plant in the treatment of asthma, petroleum ether, ethanol, and water extracts of the fruit of the plant were extracted. It was determined that the petroleum ether extracts of the fruits of the plant suppressed catalepsy, induced by clonidine. In addition, the petroleum ether extract of the fruit of the plant had a reducing effect on the increase in eosinophils and leukocyte cells caused by milk allergen, and also showed reducing effects on histamine­induced contractions. Considering the experimental results of this study, it was reported that the petroleum ether extract of the fruit of the plant could prevent the symptoms caused by asthma [28]. Carica papaya leaves are a medicinal plant used in traditional medicine to suppress inflammation. The therapeutic effect of Carica papaya leaves was investigated in an ovalbumin-induced asthma mouse model. The application of Carica pa- paya leaves extract to these asthma model mice reduced the infiltration of inflammatory cells in the lungs of the animals and also prevented alveolar thickening. In this study, it was determined that the extract of Carica papaya leaves reduced the number of leuko­cytes in the bronchoalveolar lavage fluid and in the blood of asthma model animals. It was also shown that the application of the plant extract suppressed the expression levels of IL-4, NF-ĸB, iNOS, TNF-α, IL-5, and eotaxin, thereby improving inflammation levels [29]. The antioxidant and anti-inflammatory effects of ethanol extracts of Paeonia and Schisan- dra plants on rats with asthma model were investigated in a scientific study. It was deter­mined that after the application of ethanol extracts of Paeonia and Schisandra plants, eo­sinophils in the tracheal tissues of asthma model rats was reduced and that it mediated healing in the mucosal tissue. In vivo, it was shown that the application of ethanol ex­tracts of the plants caused an increase in the antioxidant levels of rats, an increase in serum and erythrocyte SOD activity, and a decrease in MDA levels. It was reported that the application of ethanol extracts of Paeonia and Schisandra plants reduced NF-κB p65 protein expression in asthma model rats, and therefore, according to the findings of this study, Paeonia and Schisandra medicinal plants mediate antioxidant effects in vivo and can be used to treat asthma because they prevent the development of inflammation [30]. In the study investigating the therapeutic efficacy of the ethanol extract of the Viola man- dshurica W. Becker plant in an asthma mouse model, induced by ovalbumin, it was deter­mined that the application of the plant extract mediated a decrease in the levels of IgE, IL-13, and IL-4 in the blood serum and bronchoalveolar lavage fluid of the animals and prevented eosinophilia and mucus secretion. It was predicted that the ethanol extract of this plant is a medicinal plant that can be used in the treatment of asthma and can be a useful lead material for the development of asthma drugs [31]. It has been shown that the
372 Serkan Kapancik, Atteneri López Arencibia, and Burak Tuzun
ethanol extract of the Polyscias fruticosa plant may be useful in asthma due to its antihis­taminic and mast cell stabilizing effects in an ovalbumin-mediated asthma model in guinea pigs. It has been determined that the application of the ethanol extract of the Poly- scias fruticosa plant to the animal model has a reducing effect against histamine-induced bronchospasm, reducing the recovery time and preventing mast cell degranulation [32]. Perilla frutescens (L.) Britton is used as a medicinal plant among the public for the treat­ment of asthma. It has been determined that the use of Perilla leaf extract is effective in reducing cells and cytokines related to inflammation in bronchoalveolar lavage fluid and plays a positive role in the healing of lung tissue, and that it has a role in the suppression of inflammation on the airway in the mouse asthma model, induced with ovalbumin. It has been shown that Perilla leaf extract mediates the inhibition of inflammation in RBL­2H3 cells, induced by antigen, and in human peripheral blood mononuclear cells, induced with ovalbumin. In addition, in the gene expression analyses performed in vivo and in vitro, it has been determined that Perilla leaf extract reduces the expressions of genes related to inflammation and phosphorylates the proteins synthesized from these genes, which is effective in eliminating inflammatory effects. Based on the data obtained from the findings, the study concluded that the use of Perilla leaf extract has a therapeutic ef­fect in inhibiting allergic inflammation [33]. Aster yomena is a traditionally used medici­nal plant. It is used especially in the treatment of asthma, cough, and insect bites. In a study investigating the therapeutic effect of the Aster yomena plant for asthma, it was shown that the application of the alcohol extract of the plant in a mouse asthma model, created with ovalbumin, suppressed the levels of enzymes involved in the production of inflammatory mediators and thus produced therapeutic effects on asthma. However, it was reported that there was a decrease in the levels of cytokines and eosinophil counts in the bronchoalveolar lavage fluid after the application of the plant extract to asthma model mice. It was determined that the Aster yomena plant mediated healing in the lungs by eliminating the sensitivity on the respiratory tract. Based on these findings, it was stated that the Aster yomena plant is a natural agent that can be used for the treatment of bronchial asthma [34]. Duchesnea chrysantha plant is a medicinal plant class with anti­oxidant properties and anti-inflammatory therapeutic effects. In the study investigating the disease-treating effects of Duchesnea chrysantha plant in an asthma mouse model, created through ovalbumin, first, the Duchesnea chrysantha plant was pulverized and ethanol extract was obtained. It was shown that Duchesnea chrysantha plant extract me­diated the suppression of leukocytosis and eosinophilia in the bronchoalveolar lavage fluid of asthma model animal and inhibited mucus secretion. Duchesnea chrysantha plant extract suppressed the expression of IL-5, IL-13, IL-4, and eotaxin from inflamma­tion-related factors. It was reported that results indicate the anti-asthmatic effect of Duch- esnea chrysantha plant extract [35]. It is known that Nigella sativa has an antihistamine and a relaxant effect on tracheal chains. In addition, the effects of boiled Nigella sativa seed extract on asthma have also been investigated. In the study, asthma patients were divided into two groups and the first group was given the plant extract and the other group was given a placebo solution. At the beginning of the treatment and twice at 45-