Pathophysiology to Phenotype in the Asthma of Obesity

Abstract

Obesity affects numerous diseases, including asthma, for reasons that remain incompletely understood. Recent research suggests that the asthma of obesity is not a single disease, and that it breaks out into at least two distinct phenotypes. One phenotype is conventional allergic asthma modulated by obesity, whereas another arises solely due to the presence of obesity. The latter is postulated to be a consequence of the chronic lung compression caused by the obese chest wall in individuals with particularly collapsible lungs. Allergic obese asthma, on the other hand, appears to result from the way that obesity affects the immune system, which we hypothesize can be understood in terms of effects on the dynamic regulation of the inflammatory response.

Keywords: acute respiratory distress syndrome; allergic inflammation; computational model; lung mechanics; lung volume.

Figure 1.

(A) A minimal model of the immune system that can exhibit a twitch-like response to the detection of a threat by sentinel cells (see the online supplement for technical details). (B) Response of the system under “baseline” conditions (solid lines) and during obesity (dashed lines), when the inflammatory milieu is increased, while the functional status of the immune system is decreased (see main text for details). Plus sign indicates pathways that are up-regulating; minus sign indicates down-regulation. Note that the latter applies to the pathways governed by the rate constants, K_S0, K_P0, and K_A0, which indicate compartment sinks. K_A0 = sink rate-constant for anti-inflammatory cells (arbitrary units); K_AD = inhibitory rate-constant of antiinflammatory cells on tissue damage (arbitrary units); K_AP = inhibitory rate-constant of antiinflammatory cells on proinflammatory cells (arbitrary units); K_DA = stimulatory rate-constant of tissue damage on antiinflammatory cells (arbitrary units); K_DP = stimulatory rate-constant of tissue damage on proinflammatory cells (arbitrary units); K_P0 = sink rate-constant for proinflammatory cells (arbitrary units); K_PD = stimulatory rate-constant of proinflammatory cells on tissue damage (arbitrary units); K_S0 = sink rate-constant for sentinel cells (arbitrary units); K_SP = stimulatory rate-constant of sentinel cells on proinflammatory cells (arbitrary units); τ = time delay of antiinflammatory cell action on tissue damage and proinflammatory cells (arbitrary units).