Asthma is a chronic disorder affecting millions of people worldwide. The prevalence of asthma is around 300 million and is expected to increase another 100 million by 2025. Obesity, on the other hand, also affects a large number of individuals. Overweight in adults is defined when body mass index (BMI) is between 25 to 30 kg/m2 and obesity when the BMI >30 kg/m2. It has been a matter of interest for researchers to find a relation between these two conditions. This knowledge will provide a new insight into the management of both conditions. At present, obese asthma patients may be considered a special category and it is important to assess the impact of management of obesity on asthma symptoms.
KEY WORDS: Asthma, body mass index, obesity.
EFFECT OF OBESITY
Physiological consequences
Obesity usually causes a restrictive effect on the lungs. Ricard et al. (2006) has shown that there is a linear relation of decreased lung volumes and BMI.[27] At a BMI of 30 kg/m2, functional residual capacity (FRC) was reduced to 75% and expiratory reserve volume (ERV) reduced to 40% that of a lean individual with a BMI of 20 kg/m2. More reduction in lung volumes was seen in overweight and mildly obese individuals. There is a moderate reduction in total lung capacity (TLC) and greater reduction of functional residual capacity (FRC).[19] A majority of the morbid obese individuals breathe around the closing volume.[28,29] Moreover, Fredberg et al. (1997) and other similar studies showed that decrease in FRC and tidal volumes leads to small cycling rates, leading to the conversion of airway smooth muscle from rapid cycle actin-myosin cross bridges to slow cycle latch bridges. The attainment of the latch state in obese asthmatics, due to an increased frequency of detachment rate of actin-myocin may be considered a reason for persistent obstruction in asthmatic airways. Increased airway responsiveness has been found to be associated with the latch state of airway smooth muscles.[30–32] Moreover, breathing around the closing volume may enhance these effects.[32–35] Some studies have shown a decrease in the forced expiratory flow in the mid portion of FVC (FEF25-75) in obese individuals. Litonjua et al., (1999) in their study, found that t he FEF25-75/FVC ratio is independently associated with increase methacholine responsiveness of the airways. Reduction in lung volumes is proportionate to the degree of obesity. Moreover, these physiological changes can be reversed on reduction of weight. Respiratory resistance increases in obese individuals, but when airway resistance is calculated by adjusting for lung volumes, it was found to be within normal limits. It is possible that other mechanisms, apart from mechanical effect, may lead to increased airway resistance, like airway remodeling, peripheral airway obstruction etc. This hypothesis needs further studies for confirmation. Therefore, obesity did not cause obstruction of airways and moreover, FEV1 to FVC ratio remained either normal or increased.[19] Wang and his colleagues (2006) have shown increased airway hyper responsiveness with increase BMI.[41] However, Nicolacakis et al. (2008) showed that obesity per se does not alter bronchial reactivity. This study stated that obesity and asthma independently affect the function of the lungs.
Moreover, there is reduction of respiratory system compliance. This may be due to excess soft tissue weight compressing the thoracic cage, fatty infiltration of the chest wall, and an increase in pulmonary blood volume in obese individuals. Cournand et al. (1954) shown that there is increased oxygen cost of breathing with decreased lung compliance. Sin et al. (2002) found that increase in obesity is a subjective perception of dyspnea.[49] Therefore, obesity causes a reduction in respiratory system compliance and lung volumes, leading to alteration in pulmonary blood volume, and a ventilation–perfusion mismatch.
Inflammatory consequences
In obese individuals, adepocytes act as an active endocrine organ, with increased inflammatory activity. Moreover, adepocytes may recruit other inflammatory cells and augment inflammatory responses.
Both asthma and obesity are associated with an inflammatory state. Along with increased inflammatory cells, there is also an increase in inflammatory mediators in obese individuals. Several inflammatory mediators like TNF-α, interleukin-6, interleukin 18, CRP etc., have been found to be increased.[19] Mohamed-Ali et al. (1997) has shown that IL-6 and TNFα were constitutively expressed by adipocytes.[50] Tsigos et al. (1999) showed that increased levels of IL6 and TNFα could be correlated with total fat mass, especially abdominal obesity.[51] Espostio et al. (2003), in their study have shown that medical weight loss in obese women resulted in a decrease of IL-6, IL-18 and CRP levels to a significant extent. Striz et al. (1999) showed that TNF-α increases IL-4 mRNA production while IL-4 subsequently decreases TNF-α production. Similarly, Salvi et al. (1999) found that TNF-α also increases production of IL-5 by bronchial epithelial cells. Gosset et al. (1992) and Yokoyama et al. (1995), in their separate studies, showed that IL-6 production increased in asthma and has been related to stimulation with histamine, IL-4, TNF- α, and IL-1.[55,56] It has been found that IL-6 may be responsible for the IL-4 mediated IgE production. However, these markers are more closely related to central obesity. Thuesen et al. has shown that insulin resistance in centrally obese patients is more closely related to asthma like symptoms than obesity or BMI itself.
Hormones
Obesity results in changes in the level of energy regulating hormones from adepocytes. Leptin and adiponectin are two hormones of this type released by adepocytes.
Leptin, also known as the satiety hormone works as a proinflammatory mediator.[19] Leptin is coded by the Ob gene. Sierra-Honigmann and collegues (1998) showed that leptin shares a structural similarity with long-chain helical cytokines, like IL-6, and has been found to be associated with proliferation and activation of T-cells, recruitment and activation of monocytes and macrophages, and promotes angiogenesis.[59] Shore et al. (2005) sensitized and challenged lean BALB/cJ mice with ovalbumin and then infused either saline or leptin subcutaneously. They found that after leptin infusion, serum leptin levels increased, with associated enhancement of airway hyperresponsiveness (AHR), and an increase in serum IgE following inhaled ovalbumin challenge. However, these changes were not observed with saline infusion. Similar studies in animals have also shown that leptin treatment leads to increase in allergen induced airway hyperresponsivness. However, there is no increase in eosinophil influx or Th2 cytokine expression. This suggests that leptin works through a mechanism that is independent of Th2 response. Studies have also shown increased levels of leptin in patients with asthma. However, certain studies showed that leptin has a significant immunomodulatory role, irrespective of body mass.
Adiponectin is an insulin sensitizing hormone released by adipocytes. It has anti-inflammatory effects and its levels decrease in obese individuals. Adiponectin acts on macrophages and monocytes to inhibit production of proinflammatory cytokines and to augment IL-10 and IL-1 receptor antagonist expression. Shore et al. (2006) in their animal study in mice showed that exogenous administration of adiponectin results in an almost complete suppression of allergen-induced AHR, airway inflammation, and Th2 cytokine expression.[65] Decline in the mRNA expression of all 3 adeponectin receptors in the lungs, after allergen sensitization and challenge in mice, suggests that asthma may be a adiponectin resistance state.[65] Kadowaki et al. (2008) and similar studies showed obesity-related decline in adiponectin. Shore et al. (2006) showed additional decline in serum adiponectin with allergen challenge. Therefore, obese patients with asthma may have defects in this important immunomodulatory pathway that augments the effects of an allergen challenge.
Some studies have shown an increased association of obesity with asthma among women, compared to men. This may be due to hormonal differences, mostly attributable to the sex hormone estrogen. Troisi et al., in their study of the relation between menopause, postmenopausal hormone replacement therapy (HRT) and asthma has shown significantly increased relative risk of incident asthma in women on HRT (RR 1.49). Moreover, studies have shown that estrogen increases IL-4 and IL-13 production and increases eosinophil recruitment and degranulation, which are also observed in asthma patients.
Co-morbidities
Several co-morbidities have been associated with obesity and it is supposed to be a contributing factor in asthma symptoms.
Obesity is commonly associated with dyslipedemia. Animal studies have shown that a high-cholesterol diet promotes Th2 inflammation in mouse models of asthma. However, this can be reversed by a lipid lowering agent. Al-Shawwa and collegues (2006), in their study, showed a higher prevalence of asthma in children with high serum cholesterol. However, the study population was small and the results need further confirmation.
GERD and sleep disordered breathing (SDB) are also important co-morbid conditions in obesity. GERD and SDB are thought to increase the risk for asthma. Gunnbjornsdottir et al. (2004) and Sluit et al. (2005), in separate studies, showed that habitual snoring, or SDB did not substantially affect the relationship between obesity and asthma, when adjusted for GERD.[74,75] Therefore, an increased risk of asthma in the obese may be independent of GERD and SDB. When a person adopts the supine posture, there is further reduction of FRC in the obese which may thus exacerbate asthma symptoms. Moreover, continuous positive airway pressure, a treatment used extensively in the treatment of SDB, elevates the FRC, improving the quality of life in an asthma patient.More studies are required in this context to confirm or refute this relation.
Al-Shawwa and colleagues (2007) reported a higher prevalence of insulin resistance among obese children with asthma, compared with obese children without asthma. The study included a small number of subjects and needs further confirmation. Moreover, studies have shown that only the subset of obese individuals with central adiposity and insulin resistance demonstrated enhanced systemic inflammation.Thuesen et al. (2009) showed that insulin resistance was associated with incident wheezing (OR 1.87, 95% CI 1.38-2.54) and asthma-like symptoms (OR 1.61, 95% CI 1.23-2.10), and was a stronger risk factor for asthma than obesity.
KEY WORDS: Asthma, body mass index, obesity.
EFFECT OF OBESITY
Physiological consequences
Obesity usually causes a restrictive effect on the lungs. Ricard et al. (2006) has shown that there is a linear relation of decreased lung volumes and BMI.[27] At a BMI of 30 kg/m2, functional residual capacity (FRC) was reduced to 75% and expiratory reserve volume (ERV) reduced to 40% that of a lean individual with a BMI of 20 kg/m2. More reduction in lung volumes was seen in overweight and mildly obese individuals. There is a moderate reduction in total lung capacity (TLC) and greater reduction of functional residual capacity (FRC).[19] A majority of the morbid obese individuals breathe around the closing volume.[28,29] Moreover, Fredberg et al. (1997) and other similar studies showed that decrease in FRC and tidal volumes leads to small cycling rates, leading to the conversion of airway smooth muscle from rapid cycle actin-myosin cross bridges to slow cycle latch bridges. The attainment of the latch state in obese asthmatics, due to an increased frequency of detachment rate of actin-myocin may be considered a reason for persistent obstruction in asthmatic airways. Increased airway responsiveness has been found to be associated with the latch state of airway smooth muscles.[30–32] Moreover, breathing around the closing volume may enhance these effects.[32–35] Some studies have shown a decrease in the forced expiratory flow in the mid portion of FVC (FEF25-75) in obese individuals. Litonjua et al., (1999) in their study, found that t he FEF25-75/FVC ratio is independently associated with increase methacholine responsiveness of the airways. Reduction in lung volumes is proportionate to the degree of obesity. Moreover, these physiological changes can be reversed on reduction of weight. Respiratory resistance increases in obese individuals, but when airway resistance is calculated by adjusting for lung volumes, it was found to be within normal limits. It is possible that other mechanisms, apart from mechanical effect, may lead to increased airway resistance, like airway remodeling, peripheral airway obstruction etc. This hypothesis needs further studies for confirmation. Therefore, obesity did not cause obstruction of airways and moreover, FEV1 to FVC ratio remained either normal or increased.[19] Wang and his colleagues (2006) have shown increased airway hyper responsiveness with increase BMI.[41] However, Nicolacakis et al. (2008) showed that obesity per se does not alter bronchial reactivity. This study stated that obesity and asthma independently affect the function of the lungs.
Moreover, there is reduction of respiratory system compliance. This may be due to excess soft tissue weight compressing the thoracic cage, fatty infiltration of the chest wall, and an increase in pulmonary blood volume in obese individuals. Cournand et al. (1954) shown that there is increased oxygen cost of breathing with decreased lung compliance. Sin et al. (2002) found that increase in obesity is a subjective perception of dyspnea.[49] Therefore, obesity causes a reduction in respiratory system compliance and lung volumes, leading to alteration in pulmonary blood volume, and a ventilation–perfusion mismatch.
Inflammatory consequences
In obese individuals, adepocytes act as an active endocrine organ, with increased inflammatory activity. Moreover, adepocytes may recruit other inflammatory cells and augment inflammatory responses.
Both asthma and obesity are associated with an inflammatory state. Along with increased inflammatory cells, there is also an increase in inflammatory mediators in obese individuals. Several inflammatory mediators like TNF-α, interleukin-6, interleukin 18, CRP etc., have been found to be increased.[19] Mohamed-Ali et al. (1997) has shown that IL-6 and TNFα were constitutively expressed by adipocytes.[50] Tsigos et al. (1999) showed that increased levels of IL6 and TNFα could be correlated with total fat mass, especially abdominal obesity.[51] Espostio et al. (2003), in their study have shown that medical weight loss in obese women resulted in a decrease of IL-6, IL-18 and CRP levels to a significant extent. Striz et al. (1999) showed that TNF-α increases IL-4 mRNA production while IL-4 subsequently decreases TNF-α production. Similarly, Salvi et al. (1999) found that TNF-α also increases production of IL-5 by bronchial epithelial cells. Gosset et al. (1992) and Yokoyama et al. (1995), in their separate studies, showed that IL-6 production increased in asthma and has been related to stimulation with histamine, IL-4, TNF- α, and IL-1.[55,56] It has been found that IL-6 may be responsible for the IL-4 mediated IgE production. However, these markers are more closely related to central obesity. Thuesen et al. has shown that insulin resistance in centrally obese patients is more closely related to asthma like symptoms than obesity or BMI itself.
Hormones
Obesity results in changes in the level of energy regulating hormones from adepocytes. Leptin and adiponectin are two hormones of this type released by adepocytes.
Leptin, also known as the satiety hormone works as a proinflammatory mediator.[19] Leptin is coded by the Ob gene. Sierra-Honigmann and collegues (1998) showed that leptin shares a structural similarity with long-chain helical cytokines, like IL-6, and has been found to be associated with proliferation and activation of T-cells, recruitment and activation of monocytes and macrophages, and promotes angiogenesis.[59] Shore et al. (2005) sensitized and challenged lean BALB/cJ mice with ovalbumin and then infused either saline or leptin subcutaneously. They found that after leptin infusion, serum leptin levels increased, with associated enhancement of airway hyperresponsiveness (AHR), and an increase in serum IgE following inhaled ovalbumin challenge. However, these changes were not observed with saline infusion. Similar studies in animals have also shown that leptin treatment leads to increase in allergen induced airway hyperresponsivness. However, there is no increase in eosinophil influx or Th2 cytokine expression. This suggests that leptin works through a mechanism that is independent of Th2 response. Studies have also shown increased levels of leptin in patients with asthma. However, certain studies showed that leptin has a significant immunomodulatory role, irrespective of body mass.
Adiponectin is an insulin sensitizing hormone released by adipocytes. It has anti-inflammatory effects and its levels decrease in obese individuals. Adiponectin acts on macrophages and monocytes to inhibit production of proinflammatory cytokines and to augment IL-10 and IL-1 receptor antagonist expression. Shore et al. (2006) in their animal study in mice showed that exogenous administration of adiponectin results in an almost complete suppression of allergen-induced AHR, airway inflammation, and Th2 cytokine expression.[65] Decline in the mRNA expression of all 3 adeponectin receptors in the lungs, after allergen sensitization and challenge in mice, suggests that asthma may be a adiponectin resistance state.[65] Kadowaki et al. (2008) and similar studies showed obesity-related decline in adiponectin. Shore et al. (2006) showed additional decline in serum adiponectin with allergen challenge. Therefore, obese patients with asthma may have defects in this important immunomodulatory pathway that augments the effects of an allergen challenge.
Some studies have shown an increased association of obesity with asthma among women, compared to men. This may be due to hormonal differences, mostly attributable to the sex hormone estrogen. Troisi et al., in their study of the relation between menopause, postmenopausal hormone replacement therapy (HRT) and asthma has shown significantly increased relative risk of incident asthma in women on HRT (RR 1.49). Moreover, studies have shown that estrogen increases IL-4 and IL-13 production and increases eosinophil recruitment and degranulation, which are also observed in asthma patients.
Co-morbidities
Several co-morbidities have been associated with obesity and it is supposed to be a contributing factor in asthma symptoms.
Obesity is commonly associated with dyslipedemia. Animal studies have shown that a high-cholesterol diet promotes Th2 inflammation in mouse models of asthma. However, this can be reversed by a lipid lowering agent. Al-Shawwa and collegues (2006), in their study, showed a higher prevalence of asthma in children with high serum cholesterol. However, the study population was small and the results need further confirmation.
GERD and sleep disordered breathing (SDB) are also important co-morbid conditions in obesity. GERD and SDB are thought to increase the risk for asthma. Gunnbjornsdottir et al. (2004) and Sluit et al. (2005), in separate studies, showed that habitual snoring, or SDB did not substantially affect the relationship between obesity and asthma, when adjusted for GERD.[74,75] Therefore, an increased risk of asthma in the obese may be independent of GERD and SDB. When a person adopts the supine posture, there is further reduction of FRC in the obese which may thus exacerbate asthma symptoms. Moreover, continuous positive airway pressure, a treatment used extensively in the treatment of SDB, elevates the FRC, improving the quality of life in an asthma patient.More studies are required in this context to confirm or refute this relation.
Al-Shawwa and colleagues (2007) reported a higher prevalence of insulin resistance among obese children with asthma, compared with obese children without asthma. The study included a small number of subjects and needs further confirmation. Moreover, studies have shown that only the subset of obese individuals with central adiposity and insulin resistance demonstrated enhanced systemic inflammation.Thuesen et al. (2009) showed that insulin resistance was associated with incident wheezing (OR 1.87, 95% CI 1.38-2.54) and asthma-like symptoms (OR 1.61, 95% CI 1.23-2.10), and was a stronger risk factor for asthma than obesity.
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