Emerging Comorbidities in Adult Asthma: Risks, Clinical Associations, and Mechanisms

Table 2

Comorbidities and their mechanistic links to asthma.

Comorbidities and their characteristic features/mechanisms	Mediators	Link of mechanism to asthma	Ref.
Obesity, metabolic syndrome, diabetes
Adverse in utero conditions (such as maternal obesity)		Adverse conditions may induce, for example, epigenetic changes in foetus and lead to modified activity of genes important for immune system/metabolism.	[129–133]
Systemic inflammation and; inflammasome activation	IL-6, CRP,; TNF-α; IL-1β	IL-6 and CRP associated with reduced lung function. IL-6 may promote Th17 differentiation and severe neutrophilic asthma. IL-1β and IL-17 linked with development of AHR.	[138, 140, 143, 144, 154, 157]
Adipokine leptin elevated	Leptin	Airway reactivity correlated with visceral fat leptin expression. Adipokines may have direct effects on airways.	[158, 161–163]
Hyperglycemia/hyperinsulinemia	Glucose,; insulin	Glucose and insulin may have direct effects on lungs promoting airway remodelling and AHR.	[179, 180, 182, 185]
Mechanical effects of obesity		Altered lung mechanics and dysfunction of peripheral airways in obese subjects: genetic properties of the airway wall may determine whether asthma develops.	[191–193]
Mitochondrial dysfunction/oxidative stress	Oxidants	Oxidative stress, for example, damages airway epithelia, modifies expression of inflammatory genes and has many deleterious effects in asthma.	[194, 199–201, 220]
Increased ADMA (inhibition of NOS)	ADMA	Decreased ratio of L-arg/ADMA was associated with worse outcome of asthma in obese patients. Effects of ADMA on asthma may be mediated by oxidants.	[202–204, 207, 209, 210]
Coronary heart disease
Upregulated leukotrienes and 5-LO	LTs; 5-LO	CysLTs are derived from 5-LO activity and well-known mediators of bronchoconstriction and mucus production.	[215–217]
Increased ADMA (inhibition of NOS)	ADMA	See the above effects of increased ADMA on asthma.	[207–210]
Depression
Systemic inflammation and inflammasome activation	IL-6, CRP,; TNF-, IL-1	See the above effects of systemic inflammation on asthma. Inflammatory cytokines may also generate symptoms of depression. In mice studies IL-1 upregulated serotonin transporter gene.	[149–151, 155, 156]
Increased ADMA (inhibition of NOS)	ADMA	See the above effects of increased ADMA on asthma.	[205–207, 209, 210]

AHR = airway hyperresponsiveness, ADMA = asymmetric dimethyl arginine, NOS = nitric oxide synthase, HPA = hypothalamic-pituitary-adrenal, 5-LO = 5-lipoxygenase, GR = glucocorticoid, L-arg = L-arginine, LT = leukotriene, cysLT = cysteinyl leukotriene, IL = interleukin, TNF = tumor necrosis factor, and CRP = C-reactive protein.