Isometric spiracular scaling in scarab beetles-implications for diffusive and advective oxygen transport.

The scaling of respiratory structures has been hypothesized to be a major driving factor in the evolution of many aspects of animal physiology. Here, we provide the first assessment of the scaling of the spiracles in insects using 10 scarab beetle species differing 180× in mass, including some of the most massive extant insect species. Using X-ray microtomography, we measured the cross-sectional area and depth of all eight spiracles, enabling the calculation of their diffusive and advective capacities. Each of these metrics scaled with geometric isometry. Because diffusive capacities scale with lower slopes than metabolic rates, the largest beetles measured require 10-fold higher PO2 gradients across the spiracles to sustain metabolism by diffusion compared to the smallest species. Large beetles can exchange sufficient oxygen for resting metabolism by diffusion across the spiracles, but not during flight. In contrast, spiracular advective capacities scale similarly or more steeply than metabolic rates, so spiracular advective capacities should match or exceed respiratory demands in the largest beetles. These data illustrate a general principle of gas exchange: scaling of respiratory transport structures with geometric isometry diminishes the potential for diffusive gas exchange but enhances advective capacities; combining such structural scaling with muscle-driven ventilation allows larger animals to achieve high metabolic rates when active.

Gas exchange and dive behaviour in the diving beetle Platynectes decempunctatus (Coleoptera: Dytiscidae).

Many aquatic insects use bubbles on the body surface to store and supply O2 for their dives. There are two types of bubbles: air stores, which store O2 gained from air at the surface, and gas gills that allow passive extraction of O2 from water. Many insects using air stores and gas gills return to the surface to replenish their bubbles and, therefore, their requirement for O2 influences dive behaviour. In this study, we investigate gas exchange and dive behaviour in the diving beetle Platynectes decempunctatus that uses a sub-elytral air store and a small compressible gas gill. We measure the PO2 within the air store during tethered dives, as well as the amount of O2 exchanged during surfacing events. Buoyancy experiments monitor the volume of gas in the gas gill and how it changes during dives. We also directly link O2-consumption rate at three temperatures (10, 15 and 20 °C) with dive duration, surfacing frequency and movement activity. These data are incorporated in a gas exchange model, which shows that the small gas gill of P. decempunctatus contributes less than 10% of the total O2 used during the dive, while up to 10% is supplied by cutaneous uptake.

A 3D-1D coupled blood flow and oxygen transport model to generate microvascular networks.

In this work, we introduce an algorithmic approach to generate microvascular networks starting from larger vessels that can be reconstructed without noticeable segmentation errors. Contrary to larger vessels, the reconstruction of fine-scale components of microvascular networks shows significant segmentation errors, and an accurate mapping is time and cost intense. Thus there is a need for fast and reliable reconstruction algorithms yielding surrogate networks having similar stochastic properties as the original ones. The microvascular networks are constructed in a marching way by adding vessels to the outlets of the vascular tree from the previous step. To optimise the structure of the vascular trees, we use Murray's law to determine the radii of the vessels and bifurcation angles. In each step, we compute the local gradient of the partial pressure of oxygen and adapt the orientation of the new vessels to this gradient. At the same time, we use the partial pressure of oxygen to check whether the considered tissue block is supplied sufficiently with oxygen. Computing the partial pressure of oxygen, we use a 3D-1D coupled model for blood flow and oxygen transport. To decrease the complexity of a fully coupled 3D model, we reduce the blood vessel network to a 1D graph structure and use a bi-directional coupling with the tissue which is described by a 3D homogeneous porous medium. The resulting surrogate networks are analysed with respect to morphological and physiological aspects.

Axial variation of deoxyhemoglobin density as a source of the low-frequency time lag structure in blood oxygenation level-dependent signals.

Perfusion-related information is reportedly embedded in the low-frequency component of a blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. The blood-propagation pattern through the cerebral vascular tree is detected as an interregional lag variation of spontaneous low-frequency oscillations (sLFOs). Mapping of this lag, or phase, has been implicitly treated as a projection of the vascular tree structure onto real space. While accumulating evidence supports the biological significance of this signal component, the physiological basis of the "perfusion lag structure," a requirement for an integrative resting-state fMRI-signal model, is lacking. In this study, we conducted analyses furthering the hypothesis that the sLFO is not only largely of systemic origin, but also essentially intrinsic to blood, and hence behaves as a virtual tracer. By summing the small fluctuations of instantaneous phase differences between adjacent vascular regions, a velocity response to respiratory challenges was detected. Regarding the relationship to neurovascular coupling, the removal of the whole lag structure, which can be considered as an optimized global-signal regression, resulted in a reduction of inter-individual variance while preserving the fMRI response. Examination of the T2* and S0, or non-BOLD, components of the fMRI signal revealed that the lag structure is deoxyhemoglobin dependent, while paradoxically presenting a signal-magnitude reduction in the venous side of the cerebral vasculature. These findings provide insight into the origin of BOLD sLFOs, suggesting that they are highly intrinsic to the circulating blood.

Systemic Oxygen Transport with Rest, Exercise, and Hypoxia: A Comparison of Humans, Rats, and Mice.

The objective of this article is to compare and contrast the known characteristics of the systemic O2 transport of humans, rats, and mice at rest and during exercise in normoxia and hypoxia. This analysis should help understand when rodent O2 transport findings can-and cannot-be applied to human responses to similar conditions. The O2 -transport system was analyzed as composed of four linked conductances: ventilation, alveolo-capillary diffusion, circulatory convection, and tissue capillary-cell diffusion. While the mechanisms of O2 transport are similar in the three species, the quantitative differences are naturally large. There are abundant data on total O2 consumption and on ventilatory and pulmonary diffusive conductances under resting conditions in the three species; however, there is much less available information on pulmonary gas exchange, circulatory O2 convection, and tissue O2 diffusion in mice. The scarcity of data largely derives from the difficulty of obtaining blood samples in these small animals and highlights the need for additional research in this area. In spite of the large quantitative differences in absolute and mass-specific O2 flux, available evidence indicates that resting alveolar and arterial and venous blood PO2 values under normoxia are similar in the three species. Additionally, at least in rats, alveolar and arterial blood PO2 under hypoxia and exercise remain closer to the resting values than those observed in humans. This is achieved by a greater ventilatory response, coupled with a closer value of arterial to alveolar PO2 , suggesting a greater efficacy of gas exchange in the rats. © 2018 American Physiological Society. Compr Physiol 8:1537-1573, 2018.

Convective oxygen transport during development in embryos of the snapping turtle Chelydra serpentina.

This study investigated the maturation of convective oxygen transport in embryos of the snapping turtle (Chelydra serpentina). Measurements included: mass, oxygen consumption (V̇O2 ), heart rate, blood oxygen content and affinity and blood flow distribution at 50%, 70% and 90% of the incubation period. Body mass increased exponentially, paralleled by increased cardiac mass and metabolic rate. Heart rate was constant from 50% to 70% incubation but was significantly reduced at 90% incubation. Hematocrit and hemoglobin concentration were constant at the three points of development studied but arteriovenous difference doubled from 50% to 90% incubation. Oxygen affinity was lower for the early 50% incubation group (stage 19) compared with all other age groups. Blood flow was directed predominantly to the embryo but was highest to the chorioallantoic membrane (CAM) at 70% incubation and was directed away from the yolk as it was depleted at 90% incubation. The findings indicate that the plateau or reduction in egg V̇O2  characteristic of the late incubation period of turtle embryos may be related to an overall reduction in mass-specific V̇O2  that is correlated with decreasing relative heart mass and plateaued CAM blood flow. Importantly, if the blood properties remain unchanged prior to hatching, as they did during the incubation period studied in the current investigation, this could account for the pattern of V̇O2 previously reported for embryonic snapping turtles prior to hatching.

Aquatic acidification: a mechanism underpinning maintained oxygen transport and performance in fish experiencing elevated carbon dioxide conditions.

Aquatic acidification, caused by elevating levels of atmospheric carbon dioxide (CO2), is increasing in both freshwater and marine ecosystems worldwide. However, few studies have examined how acidification will affect oxygen (O2) transport and, therefore, performance in fishes. Although data are generally lacking, the majority of fishes investigated in this meta-analysis exhibited no effect of elevated CO2 at the level of O2 uptake, suggesting that they are able to maintain metabolic performance during a period of acidosis. Notably, the mechanisms that fish employ to maintain performance and O2 uptake have yet to be verified. Here, we summarize current data related to one recently proposed mechanism underpinning the maintenance of O2 uptake during exposure to aquatic acidification, and reveal knowledge gaps that could be targeted for future research. Most studies have examined O2 uptake rates while fishes were resting and did not calculate aerobic scope, even though aerobic scope can aid in predicting changes to whole-animal metabolic performance. Furthermore, research is lacking on different age classes, freshwater species and elasmobranchs, all of which might be impacted by future acidification conditions. Finally, this Review further seeks to emphasize the importance of developing collaborative efforts between molecular, physiological and ecological approaches in order to provide more comprehensive predictions as to how future fish populations will be affected by climate change.

Respiratory patterns in field collected brown locust, Locustana pardalina, in the gregarious phase.

In this paper we report on the metabolic rates and respiratory patterns measured from gregarious brown locusts, Locustana pardalina, collected from the Nama Karoo region in South Africa. All five instar hopper stages and adults were collected over a three year period when significant numbers of locust swarms were seen. Flow-through respirometry was used to measure the CO2 emission from individual locusts from all the developmental stages and adults within a week of collection. Carbon dioxide emission scaled hypometrically with mass, 0.863 ±â€¯0.026. Except in the 1st and 5th instar stage there was no difference in the mass specific rate of CO2 emission (V̇CO2). These had significantly higher metabolic rates compared to the other stages which reflects their biology, with the 1st instar undergoing rapid growth and the 5th instar also undergoing rapid growth and development in preparation for becoming an adult. The 1st instars used a form of continuous gas exchange while all the other stages showed discontinuous gas exchange cycles. A clear burst phase and interburst periods could be seen. The 2nd and 3rd instars use mainly diffusion to expel CO2 and so exhibited an open form of the burst phase. There was an increase in CO2 volleys seen in the burst phase from the 4th instar stage onwards thus indicating an increased use of convection. There was no change in the duration or frequency of the discontinuous gas exchange cycles through the locust development or with body mass.

The transition from water to air in aeshnid dragonflies is associated with a change in ventilatory responses to hypoxia and hypercapnia.

Dragonflies are amphibiotic, spending most of their lives as aquatic nymphs before metamorphosing into terrestrial, winged imagoes. Both the nymph and the adult use rhythmic abdominal pumping movements to ventilate their gas exchange systems: the nymph tidally ventilates its rectal gill with water, while the imago pumps air into its tracheal system through its abdominal spiracles. The transition from water to air is known to be associated with changes in both respiratory chemosensitivity and ventilatory control in vertebrates and crustaceans, but the changes experienced by amphibiotic insects have been poorly explored. In this study, dragonfly nymphs (Anax junius) and imagoes (Anax junius and Aeshna multicolor) were exposed to hypoxia and hypercapnia while their abdominal ventilation frequency and amplitude was recorded. Water-breathing nymphs showed a significant increase in abdominal pumping frequency when breathing hypoxic water (<10 kPa O2), but no strong response to CO2, even in severe hypercapnia (up to 10 kPa CO2). In contrast, both species of air-breathing imago increased their abdominal pumping amplitude when exposed to either hypoxia or hypercapnia, but did not show any significant increase in frequency. These results demonstrate that aquatic dragonfly nymphs possess a respiratory sensitivity that is more like other water breathing animals, being sensitive to hypoxia but not hypercapnia, while their air-breathing adult form responds to both respiratory challenges, like other terrestrial insects. Shifting from ventilating a rectal gill with water to ventilating a tracheal system with air is also associated with a change in how abdominal ventilation is controlled; nymphs regulate gas exchange by varying frequency while imagoes respond by varying amplitude.

The effect of within-instar development on tracheal diameter and hypoxia-inducible factors α and ß in the tobacco hornworm, Manduca sexta.

As insects grow within an instar, body mass increases, often more than doubling. The increase in mass causes an increase in metabolic rate and hence oxygen demand. However, the insect tracheal system is hypothesized to increase only after molting and may be compressed as tissues grow within an instar. The increase in oxygen demand in the face of a potentially fixed or decreasing supply could result in hypoxia as insects near the end of an instar. To test these hypotheses, we first used synchrotron X-ray imaging to determine how diameters of large tracheae change within an instar and after molting to the next instar in the tobacco hornworm, Manduca sexta. Large tracheae did not increase in diameter within the first, second, third, and fourth instars, but increased upon molting. To determine if insects are hypoxic at the end of instars, we used the presence of hypoxia-inducible factors (HIFs) as an index. HIF-α and HIF-ß dimerize in hypoxia and act as a transcription factor that turns on genes that will increase oxygen delivery. We sequenced both of these genes and measured their mRNA levels at the beginning and end of each larval instar. Finally, we obtained an antibody to HIF-α and measured protein expression during the same time. Both mRNA and protein levels of HIFs were increased at the end of most instars. These data support the hypothesis that some insects may experience hypoxia at the end of an instar, which could be a signal for molting. SUMMARY STATEMENT: As caterpillars grow within an instar, major tracheae do not increase in size, while metabolic demand increases. At the same life stages, caterpillars increased expression of hypoxia inducible factors, suggesting that they become hypoxic near the end of an instar.

A Dynamic Model of Rescuer Parameters for Optimizing Blood Gas Delivery during Cardiopulmonary Resuscitation.

INTRODUCTION: The quality of cardiopulmonary resuscitation (CPR) has been shown to impact patient outcomes. However, post-CPR morbidity and mortality remain high, and CPR optimization is an area of active research. One approach to optimizing CPR involves establishing reliable CPR performance measures and then modifying CPR parameters, such as compressions and ventilator breaths, to enhance these measures. We aimed to define a reliable CPR performance measure, optimize the CPR performance based on the defined measure and design a dynamically optimized scheme that varies CPR parameters to optimize CPR performance. MATERIALS AND METHODS: We selected total blood gas delivery (systemic oxygen delivery and carbon dioxide delivery to the lungs) as an objective function for maximization. CPR parameters were divided into three categories: rescuer dependent, patient dependent, and constant parameters. Two optimization schemes were developed using simulated annealing method: a global optimization scheme and a sequential optimization scheme. RESULTS AND DISCUSSION: Variations of CPR parameters over CPR sequences (cycles) were analyzed. Across all patient groups, the sequential optimization scheme resulted in significant enhancement in the effectiveness of the CPR procedure when compared to the global optimization scheme. CONCLUSIONS: Our study illustrates the potential benefit of considering dynamic changes in rescuer-dependent parameters during CPR in order to improve performance. The advantage of the sequential optimization technique stemmed from its dynamically adapting effect. Our CPR optimization findings suggest that as CPR progresses, the compression to ventilation ratio should decrease, and the sequential optimization technique can potentially improve CPR performance. Validation in vivo is needed before implementing these changes in actual practice.

Impact of four different recumbencies on the distribution of ventilation in conscious or anaesthetized spontaneously breathing beagle dogs: An electrical impedance tomography study.

The aim was to examine the effects of recumbency and anaesthesia on distribution of ventilation in beagle dogs using Electrical Impedance Tomography (EIT). Nine healthy beagle dogs, aging 3.7±1.7 (mean±SD) years and weighing 16.3±1.6 kg, received a series of treatments in a fixed order on a single occasion. Conscious dogs were positioned in right lateral recumbency (RLR) and equipped with 32 EIT electrodes around the thorax. Following five minutes of equilibration, two minutes of EIT recordings were made in each recumbency in the following order: RLR, dorsal (DR), left (LLR) and sternal (SR). The dogs were then positioned in RLR, premedicated (medetomidine 0.01, midazolam 0.1, butorphanol 0.1 mg kg-1 iv) and pre-oxygenated. Fifteen minutes later anaesthesia was induced with 1 mg kg-1 propofol iv and maintained with propofol infusion (0.1-0.2 mg kg-1 minute-1 iv). After induction, the animals were intubated and allowed to breathe spontaneously (FIO2 = 1). Recordings of EIT were performed again in four recumbencies similarly to conscious state. Centre of ventilation (COV) and global inhomogeneity (GI) index were calculated from the functional EIT images. Repeated-measures ANOVA and Bonferroni tests were used for statistical analysis (p < 0.05). None of the variables changed in the conscious state. During anaesthesia left-to-right COV increased from 46.8±2.8% in DR to 49.8±2.9% in SR indicating a right shift, and ventral-to-dorsal COV increased from 49.8±1.7% in DR to 51.8±1.1% in LLR indicating a dorsal shift in distribution of ventilation. Recumbency affected distribution of ventilation in anaesthetized but not in conscious dogs. This can be related to loss of respiratory muscle tone (e.g. diaphragm) and changes in thoracic shape. Changing position of thoraco-abdominal organs under the EIT belt should be considered as alternative explanation of these findings.

Image-based computational fluid dynamics in the lung: virtual reality or new clinical practice?

The development and implementation of personalized medicine is paramount to improving the efficiency and efficacy of patient care. In the respiratory system, function is largely dictated by the choreographed movement of air and blood to the gas exchange surface. The passage of air begins in the upper airways, either via the mouth or nose, and terminates at the alveolar interface, while blood flows from the heart to the alveoli and back again. Computational fluid dynamics (CFD) is a well-established tool for predicting fluid flows and pressure distributions within complex systems. Traditionally CFD has been used to aid in the effective or improved design of a system or device; however, it has become increasingly exploited in biological and medical-based applications further broadening the scope of this computational technique. In this review, we discuss the advancement in application of CFD to the respiratory system and the contributions CFD is currently making toward improving precision medicine. The key areas CFD has been applied to in the pulmonary system are in predicting fluid transport and aerosol distribution within the airways. Here we focus our discussion on fluid flows and in particular on image-based clinically focused CFD in the ventilatory system. We discuss studies spanning from the paranasal sinuses through the conducting airways down to the level of the alveolar airways. The combination of imaging and CFD is enabling improved device design in aerosol transport, improved biomarkers of lung function in clinical trials, and improved predictions and assessment of surgical interventions in the nasal sinuses. WIREs Syst Biol Med 2017, 9:e1392. doi: 10.1002/wsbm.1392 For further resources related to this article, please visit the WIREs website.

Acute effects of temperature and hypercarbia on cutaneous and branchial gas exchange in the South American lungfish, Lepidosiren paradoxa.

The South American lungfish, Lepidosiren paradoxa inhabits seasonal environments in the Central Amazon and Paraná-Paraguay basins that undergo significant oscillations in temperature throughout the year. They rely on different gas exchange organs, such as gills and skin for aquatic gas exchange while their truly bilateral lungs are responsible for aerial gas exchange; however, there are no data available on the individual contributions of the skin and the gills to total aquatic gas exchange in L. paradoxa. Thus, in the present study we quantify the relative contributions of skin and gills on total aquatic gas exchange during warm (35°C) and cold exposure (20°C) in addition to the effects of aerial and aquatic hypercarbia on aquatic gas exchange and gill ventilation rate (fG; 25°C), respectively. Elevated temperature (35°C) caused a significant increase in the contribution of cutaneous (from 0.61±0.13 to 1.34±0.26ml. STPD.h-1kg-1) and branchial (from 0.54±0.17 to 1.73±0.53ml. STPD.h-1kg-1) gas exchange for V̇CO2 relative to the lower temperature (20°C), while V̇O2 remained relatively unchanged. L. paradoxa exhibited a greater branchial contribution in relation to total aquatic gas exchange at lower temperatures (20 and 25°C) for oxygen uptake. Aerial hypercarbia decreased branchial V̇O2 whereas branchial V̇CO2 was significantly increased. Progressive increases in aquatic hypercarbia did not affect fG. This response is in contrast to increases in pulmonary ventilation that may offset any increase in arterial partial pressure of CO2 owing to CO2 loading through the animals' branchial surface. Thus, despite their reduced contribution to total gas exchange, cutaneous and branchial gas exchange in L. paradoxa can be significantly affected by temperature and aerial hypercarbia.

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part I: Theory and model validation.

Computational predictions of aerosol transport and deposition in the human respiratory tract can assist in evaluating detrimental or therapeutic health effects when inhaling toxic particles or administering drugs. However, the sheer complexity of the human lung, featuring a total of 16 million tubular airways, prohibits detailed computer simulations of the fluid-particle dynamics for the entire respiratory system. Thus, in order to obtain useful and efficient particle deposition results, an alternative modeling approach is necessary where the whole-lung geometry is approximated and physiological boundary conditions are implemented to simulate breathing. In Part I, the present new whole-lung-airway model (WLAM) represents the actual lung geometry via a basic 3-D mouth-to-trachea configuration while all subsequent airways are lumped together, i.e., reduced to an exponentially expanding 1-D conduit. The diameter for each generation of the 1-D extension can be obtained on a subject-specific basis from the calculated total volume which represents each generation of the individual. The alveolar volume was added based on the approximate number of alveoli per generation. A wall-displacement boundary condition was applied at the bottom surface of the first-generation WLAM, so that any breathing pattern due to the negative alveolar pressure can be reproduced. Specifically, different inhalation/exhalation scenarios (rest, exercise, etc.) were implemented by controlling the wall/mesh displacements to simulate realistic breathing cycles in the WLAM. Total and regional particle deposition results agree with experimental lung deposition results. The outcomes provide critical insight to and quantitative results of aerosol deposition in human whole-lung airways with modest computational resources. Hence, the WLAM can be used in analyzing human exposure to toxic particulate matter or it can assist in estimating pharmacological effects of administered drug-aerosols. As a practical WLAM application, the transport and deposition of asthma drugs from a commercial dry-powder inhaler is discussed in Part II.

Gas Exchange Models for a Flexible Insect Tracheal System.

In this paper two models for movement of respiratory gases in the insect trachea are presented. One model considers the tracheal system as a single flexible compartment while the other model considers the trachea as a single flexible compartment with gas exchange. This work represents an extension of Ben-Tal's work on compartmental gas exchange in human lungs and is applied to the insect tracheal system. The purpose of the work is to study nonlinear phenomena seen in the insect respiratory system. It is assumed that the flow inside the trachea is laminar, and that the air inside the chamber behaves as an ideal gas. Further, with the isothermal assumption, the expressions for the tracheal partial pressures of oxygen and carbon dioxide, rate of volume change, and the rates of change of oxygen concentration and carbon dioxide concentration are derived. The effects of some flow parameters such as diffusion capacities, reaction rates and air concentrations on net flow are studied. Numerical simulations of the tracheal flow characteristics are performed. The models developed provide a mathematical framework to further investigate gas exchange in insects.

Particle transport in the human respiratory tract: formulation of a nodal inverse distance weighted Eulerian-Lagrangian transport and implementation of the Wind-Kessel algorithm for an oral delivery.

This paper is the first in a series wherein efficient computational methods are developed and implemented to accurately quantify the transport, deposition, and clearance of the microsized particles (range of interest: 2 to 10 µm) in the human respiratory tract. In particular, this paper (part I) deals with (i) development of a detailed 3D computational finite volume mesh comprising of the NOPL (nasal, oral, pharyngeal and larynx), trachea and several airway generations; (ii) use of CFD Research Corporation's finite volume Computational Biology (CoBi) flow solver to obtain the flow physics for an oral inhalation simulation; (iii) implement a novel and accurate nodal inverse distance weighted Eulerian-Lagrangian formulation to accurately obtain the deposition, and (iv) development of Wind-Kessel boundary condition algorithm. This new Wind-Kessel boundary condition algorithm allows the 'escaped' particles to reenter the airway through the outlets, thereby to an extent accounting for the drawbacks of having a finite number of lung generations in the computational mesh. The deposition rates in the NOPL, trachea, the first and second bifurcation were computed, and they were in reasonable accord with the Typical Path Length model. The quantitatively validated results indicate that these developments will be useful for (i) obtaining depositions in diseased lungs (because of asthma and COPD), for which there are no empirical models, and (ii) obtaining the secondary clearance (mucociliary clearance) of the deposited particles. Copyright © 2015 John Wiley & Sons, Ltd.

Mathematical Model of Oxygen Transport in Tuberculosis Granulomas.

Pulmonary granulomas--the hallmark of Mycobacterium tuberculosis (MTB) infection--are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution--using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis--was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment.