Human respiratory input impedance from 4 to 200 Hz: physiological and modeling considerations

Recent studies on respiratory impedance (Zrs) have predicted that at frequencies greater than 64 Hz a second resonance will occur. Furthermore, if one intends to fit a model more complicated than the simple series combination of a resistance, inertance, and compliance to Zrs data, the only way to ensure statistically reliable parameter estimates is to include data surrounding this second resonance. An additional question, however, is whether the resulting parameters are physiologically meaningful. We obtained input impedance data from eight healthy adult humans using discrete frequency forced oscillations from 4 to 200 Hz. Three resonant frequencies were seen: 8 +/- 2, 151 +/- 10, and 182 +/- 16 Hz. A seven-parameter lumped element model provided an excellent fit to the data in all subjects. This model consists of an airway resistance (Raw), which is linearly dependent on frequency, and airway inertance separated from a tissue resistance, inertance, and compliance by a shunt compliance (Cg) thought to represent gas compressibility. Model estimates of Raw and Cg were compared with those suggested by measurement of Raw and thoracic gas volume using a plethysmograph. In all subjects the model Raw and Cg were significantly lower than and not correlated with the corresponding plethysmographic measurement. We hypothesize that the statistically reliable but physiologically inconsistent parameters are a consequence of the distorting influence of airway wall compliance and/or airway quarter-wave resonance. Such factors are not inherent to the seven-parameter model.     

Inverse modeling of dog airway and respiratory system impedances

Mechanical parameters of the respiratory system are often estimated from respiratory impedances using lumped-element inverse models. One such six-element model is composed of an airway branch [with a resistance (Raw) and inertance (Iaw)] separated from a tissue branch [with a resistance (Rt), inertance (It), and compliance (Ct)] by a shunt compliance representing alveolar gas compression (Cg). Even though the airways are known to have frequency-dependent resistance and inertance, these inverse models have been composed of linear frequency-independent elements. In this study we investigated the use of inverse models where the airway branch was represented by a frequency-independent Raw and Iaw, a Raw that is linearly related to frequency and an Iaw that is independent of frequency, and a system of identical parallel tubes the impedance of which was computed from the tube radius and length. These inverse models were used to analyze airway and respiratory impedances between 2 and 1,024 Hz that were predicted from an anatomically detailed forward model. The forward model represented the airways by an asymmetrically branched network with a terminal impedance representative of known Cg, Rt, It, and Ct. For respiratory impedances between 2 and 128 Hz, all models fit the data reasonably well, and reasonably accurate estimates of Cg, Rt, It, and Ct were extracted from these data. For data above 200 Hz, however, only the multiple-tube model accurately fitted respiratory impedances (Zrs). This model fitted the Zrs data best when composed of 27 tubes, each having a radius of 0.148 cm and a length of 16.5 cm.     

Density dependence of respiratory system impedances between 5 and 320 Hz in humans

For respiratory system impedance (Zrs), the six-element model of DuBois et al. (J. Appl. Physiol. 8: 587-594, 1956) suggests three resonant frequencies (f1,f2,f3), where f1 is the result of the sum of tissue and airway inertances and tissue compliance and f2 is the result of alveolar gas compression compliance (Cg) and tissue inertance (Iti). Three such resonant frequencies have been reported in humans. However, the parameter estimates resulting from fitting this model to the data suggested that f2 and f3 were not associated with Cg and Iti but with airway acoustic properties. In the present study, we measured Zrs between 5 and 320 Hz in 10 healthy adult humans breathing room air or 80% He-20% O2 (HeO2) to gain insight as to whether airway or tissue properties are responsible for the f2 and f3. When the subjects breathed room air, f2 occurred at 170 +/- 16 (SD) Hz, and when they breathed HeO2 it occurred at 240 +/- 24 Hz. If this resonance were due to Cg and Iti it should not have been affected to this extent by the breathing of HeO2. We thus conclude that f2 is not due to tissue elements but that it is an airway acoustic resonance. Furthermore, application of the six-element model to analyze Zrs data at these frequencies is inappropriate, and models incorporating the airway acoustic properties should be used. One such model is based on the concept of equivalent length, which is defined as the length of an open-ended, cylindrical tube that has the same fundamental acoustic resonant frequency.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinome-wide RNAi screen implicates at least 5 host hepatocyte kinases in Plasmodium sporozoite infection

Plasmodium sporozoites, the causative agent of malaria, are injected into their vertebrate host through the bite of an infected Anopheles mosquito, homing to the liver where they invade hepatocytes to proliferate and develop into merozoites that, upon reaching the bloodstream, give rise to the clinical phase of infection. To investigate how host cell signal transduction pathways affect hepatocyte infection, we used RNAi to systematically test the entire kinome and associated genes in human Huh7 hepatoma cells for their potential roles during infection by P. berghei sporozoites. The three-phase screen covered 727 genes, which were tested with a total of 2,307 individual siRNAs using an automated microscopy assay to quantify infection rates and qRT-PCR to assess silencing levels. Five protein kinases thereby emerged as top hits, all of which caused significant reductions in infection when silenced by RNAi. Follow-up validation experiments on one of these hits, PKCsigma (PKCzeta), confirmed the physiological relevance of our findings by reproducing the inhibitory effect on P. berghei infection in adult mice treated systemically with liposome-formulated PKCsigma-targeting siRNAs. Additional cell-based analyses using a pseudo-substrate inhibitor of PKCsigma added further RNAi-independent support, indicating a role for host PKCsigma on the invasion of hepatocytes by sporozoites. This study represents the first comprehensive, functional genomics-driven identification of novel host factors involved in Plasmodium sporozoite infection.     

Respiratory impedance and multibreath N2 washout in healthy, asthmatic, and cystic fibrosis subjects

We measured forced expiratory volume in 1 s (FEV1), respiratory impedance (Zrs) from 4 to 60 Hz, and a multibreath N2 washout (MBNW) in 6 normal, 10 asthmatic, and 5 cystic fibrosis (CF) subjects. The MBNW were characterized by the mean dilution number (MDN) derived by a moment analysis. The Zrs spectra were characterized by the minimum resistance (Rmin), the drop in resistance (Rdrop) from 4 Hz to Rmin, and the first resonance frequency (Fr1). Measurements were repeated after bronchodilation in three normal and all asthmatic subjects. Before bronchodilation, six of the asthmatic subjects showed close to normal FEV1. The Zrs in the normal subjects showed low Rmin (1.9 +/- 0.7 cmH2O.l-1.s), Rdrop (0.4 +/- 0.4), and Fr1 (10 +/- 2 Hz). Four of the mildly obstructed asthmatic subjects had normal Zrs but elevated MDNs (i.e., abnormal ventilation distribution). The other six asthmatic subjects had significantly elevated Rmin (4.1 +/- 0.8), Rdrop (6.3 +/- 5.8), and Fr1 (34 +/- 0.4 Hz) and elevated MDNs. The CF patients had elevated Zrs features and MDNs. After bronchodilation, no changes in FEV1, MDN, or Zrs occurred in the normal subjects. All asthmatic subjects showed increased FEV1 and decreased MDN, but the Zrs was unaltered in the four asthmatic subjects whose base-line Zrs was normal. For the other six asthmatic subjects, there were large decreases in the Rmin, Rdrop, and Fr1. Finally, there was a poor correlation between the MDN and the Zrs features but high correlation between the Zrs features alone. These results imply that significant nonuniform peripheral airway obstruction can exist such that ventilation distribution is abnormal but Zrs from 4 to 60 Hz is not. Abnormalities in Zrs from 4 to 60 Hz occur only after significant overall obstruction in the peripheral and more central airways. Combining Zrs and the MBNW may permit us to infer whether the disease is predominantly in the lung periphery or in the more central airways.