Modeling nitric oxide production and transport in the human lung

Le travail présenté ici porte sur l’étude de la production et du transport du monoxyde d’azote (NO) dans le poumon humain. Le NO est une molécule dont l’implication dans des processus physiologiques n’a été mis en évidence qu’en 1987. Depuis, il a été démontré que le NO joue de nombreux rôles dans le corps humain. Le NO est un gaz labile (instable) dans les conditions physiologiques, il diffuse très facilement au travers des parois et il a une grande affinité pour l’hémoglobine. La production du NO est liée à 3 isoformes différentes de la protéine appelées synthases du NO ou NO synthases.\Doctorat en sciences, Spécialisation physiqueinfo:eu-repo/semantics/nonPublishe

Modeling nitric oxide production and transport in the human lung

Le travail présenté ici porte sur l’étude de la production et du transport du monoxyde d’azote (NO) dans le poumon humain. Le NO est une molécule dont l’implication dans des processus physiologiques n’a été mis en évidence qu’en 1987. Depuis, il a été démontré que le NO joue de nombreux rôles dans le corps humain. Le NO est un gaz labile (instable) dans les conditions physiologiques, il diffuse très facilement au travers des parois et il a une grande affinité pour l’hémoglobine. La production du NO est liée à 3 isoformes différentes de la protéine appelées synthases du NO ou NO synthases.\Doctorat en sciences, Spécialisation physiqueinfo:eu-repo/semantics/nonPublishe

Axial distribution heterogeneity of nitric oxide airway production in healthy adults.

Model simulations of nitric oxide (NO) transport considering molecular diffusion showed that the total bronchial NO production needed to reproduce a given exhaled value is deeply influenced by its axial distribution. Experimental data obtained by fibroscopy were available about proximal airway contribution (Silkoff PE, McClean PA, Caramori M, Slutsky AS. Zamel N. Respir Physiol 113: 33-38, 1998), and recent experiments using heliox instead of air gave insight on the peripheral airway production (Shin HW, Condorelli P, Rose-Gottron CM, Cooper DM, George SC. J Appl Physiol 97: 874-882, 2004; Kerckx Y, Michils A, Van Muylem A. J Appl Physiol 104: 918-924, 2008). This theoretical work aimed at obtaining a realistic distribution of NO production in healthy adults by meeting both proximal and peripheral experimental constraints. To achieve this, a model considering axial diffusion with geometrical boundaries derived from Weibel's morphometrical data was divided into serial compartments, each characterized by its axial boundaries and its part of bronchial NO production. A four-compartment model was able to meet both criteria. Two compartments were found to share all the NO production: one proximal (generations 0 and 1; 15-25% of the NO production) and one inside the acinus (proximal limit, generations 14-16; distal limit, generations 16 and 17; 75-85% of the NO production). Remarkably, this finding implies a quasi nil production in the main part of the conducting airways and in the acinar airways distal to generation 17. Given the chosen experimental outcomes and reliant on their accuracy, this very inhomogeneous distribution is likely the more realistic one that may be achieved with a "one-trumpet"-shaped model. Refinement should come from a more realistic description of the acinus structure.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acinar effect of inhaled steroid therapy evidenced by exhaled nitric oxide

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Axial distribution of nitric oxide production in unstable asthmatics

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Axial distribution of nitric oxide airway production in asthma patients.

In healthy subjects, axial distribution of nitric oxide (NO) airway production is likely heterogeneous: notably a distal peak of production in terminal bronchioles and a quasi-nil NO production in the most of the conducting airways. In asthma, few information exists about the contributions of the proximal and distal airways to NO overproduction. In 18 asthma patients, sites of constriction after methacholine and adenosine 5'-monophosphate (AMP) challenges were assessed by ventilation distribution tests with He and SF(6). The resulting decreases in fractional exhaled NO (FENO) were measured. Changes in He and SF(6) slopes indicated a pre-acinar bronchoconstriction due to AMP and a more proximal action for methacholine. FENO decreased by 38.7% and 20.2% (p<0.001) after AMP and methacholine challenges, respectively. Significant FENO decreases after AMP and methacholine implies substantial pre-acinar but also, contrary to healthy subjects, more proximal airway production. In conclusion, nitric oxide overproduction in asthma patients appears to involve the most part of the conducting airways.Journal ArticleRandomized Controlled TrialSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Airway contribution to alveolar nitric oxide in healthy subjects and stable asthma patients.

Alveolar nitric oxide (NO) concentration (Fa(NO)), increasingly considered in asthma, is currently interpreted as a reflection of NO production in the alveoli. Recent modeling studies showed that axial molecular diffusion brings NO molecules from the airways back into the alveolar compartment during exhalation (backdiffusion) and contributes to Fa(NO). Our objectives in this study were 1) to simulate the impact of backdiffusion on Fa(NO) and to estimate the alveolar concentration actually due to in situ production (Fa(NO,prod)); and 2) to determine actual alveolar production in stable asthma patients with a broad range of NO bronchial productions. A model incorporating convection and diffusion transport and NO sources was used to simulate Fa(NO) and exhaled NO concentration at 50 ml/s expired flow (Fe(NO)) for a range of alveolar and bronchial NO productions. Fa(NO) and Fe(NO) were measured in 10 healthy subjects (8 men; age 38 +/- 14 yr) and in 21 asthma patients with stable asthma [16 men; age 33 +/- 13 yr; forced expiratory volume during 1 s (FEV(1)) = 98.0 +/- 11.9%predicted]. The Asthma Control Questionnaire (Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Chest 115: 1265-1270, 1999) assessed asthma control. Simulations predict that, because of backdiffusion, Fa(NO) and Fe(NO) are linearly related. Experimental results confirm this relationship. Fa(NO,prod) may be derived by Fa(NO,prod) = (Fa(NO) - 0.08.Fe(NO))/0.92 (Eq. 1). Based on Eq. 1, Fa(NO,prod) is similar in asthma patients and in healthy subjects. In conclusion, the backdiffusion mechanism is an important determinant of NO alveolar concentration. In stable and unobstructed asthma patients, even with increased bronchial NO production, alveolar production is normal when appropriately corrected for backdiffusion.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acinar effect of inhaled steroids evidenced by exhaled nitric oxide.

The effects of inhaled corticosteroids (ICSs) on distal lung inflammation, as assessed by alveolar nitric oxide concentration (C(A)NO), are a matter of debate. Recently, a theoretic study suggested that acinar airway obstruction that is relieved by ICS treatment and associated with a decrease in fraction of exhaled nitric oxide (FeNO) concentration might, paradoxically, increase C(A)NO. This increase could be a hallmark effect of ICSs at the acinar level.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of blood redistribution on exhaled and alveolar nitric oxide: a hypergravity model study.

Alveolar (CA(NO)) and exhaled nitric oxide (FE(NO)) concentrations, mainly regarded as inflammation surrogates, may also be affected by perfusion redistribution changing alveolar transfer factor (DA(NO)). A model of blood redistribution is hypergravity, Karlsson et al. (2009b) found, at 2G, increases of 22% and 70%, for FE(NO), and CA(NO), respectively. The present study aimed at theoretically estimating the amplitude of DA(NO) changes that mimic these experimental data. An equation describing convection, diffusion and NO sources was solved in a 2-trumpet model (parallel dependent and non-dependent lung units). Acinar airways lumen reduction was also simulated. A reduction of 33% of the overall DA(NO) (-51% in the non-dependent unit) along with a 36% reduction of acinar airways lumen reproduced experimental findings. In conclusion, substantial FE(NO) and CA(NO) increases may be accounted for by a decrease of the alveolo-capillaries contact surface, here hypergravity-induced. Acinar airway constriction may also have a part in the overall FE(NO) increase.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe