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Connie C W Hsia

Publications and source records attributed to Connie C W Hsia.

At least 19 recordsLinked to original sources
PubMed2007

Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years.

Mammals native to high altitude (HA) exhibit larger lung volumes than their lowland counterparts. To test the hypothesis that adaptation induced by HA residence during somatic maturation improves pulmonary gas exchange in adulthood, male foxhounds born at sea level (SL) were raised at HA (3,800 m) from 2.5 to 7.5 mo of age and then returned to SL prior to somatic maturity while their littermates were simultaneously raised at SL. Following return to SL, all animals were trained to run on a treadmill; gas exchange and hemodynamics were measured 2.5 years later at rest and during exercise while breathing 21% and 13% O(2). The multiple inert gas elimination technique was employed to estimate ventilation-perfusion (Va/Q) distributions and lung diffusing capacity for O(2) (Dl(O(2))). There were no significant intergroup differences during exercise breathing 21% O(2). During exercise breathing 13% O(2), peak O(2) uptake and Va/Q distributions were similar between groups but arterial pH, base excess, and O(2) saturation were higher while peak lactate concentration was lower in animals raised at HA than at SL. At a given exercise intensity, alveolar-arterial O(2) tension gradient (A-aDo(2)) attributable to diffusion limitation was lower while Dlo(2) was 12-25% higher in HA-raised animals. Mean systemic arterial blood pressure was also lower in HA-raised animals; mean pulmonary arterial pressures were similar. We conclude that 5 mo of HA residence during maturation enhances long-term gas exchange efficiency and Dl(O(2)) without impacting Va/Q inequality during hypoxic exercise at SL.

Acclimatization↗
PubMed2006

Developmental signals do not further accentuate nonuniform postpneumonectomy compensatory lung growth.

Mechanical forces imposed on lung tissue constitute major stimuli for normal lung development and postpneumonectomy (PNX) compensatory growth and remodeling. Superimposing developmental signals on PNX signals augments compensatory alveolar growth but exaggerates airway-parenchymal dissociation (i.e., dysanaptic lung growth); the latter tends to offset benefits derived from the former. In adult dogs after PNX, lobar expansion and growth of the remaining lobes were markedly non-uniform (Ravikumar et al. J Appl Physiol 97:1567-1574, 2004). We hypothesized that superimposing developmental and post-PNX signals further accentuates nonuniformity of lobar growth. We used high-resolution computed tomography (HRCT) to follow regional lung expansion and growth in foxhounds undergoing right PNX at 2.5 mo of age compared with litter-matched control (Sham) animals; scans were performed 4 and 10 mo following surgery, i.e., before and after somatic maturity. Air and tissue volumes were measured in each lobe; tissue volume estimated by HRCT includes air-free tissue and blood in small vessels <1 mm. Interlobar nonuniformity of tissue volume was absent at 4 mo but evident 10 mo after PNX; growth of the remaining left lower lobe gradually lagged behind other lobes. At maturity, nonuniformity of lobar growth in pneumonectomized puppies was similar to that previously reported in pneumonectomized adults. We conclude that superimposing developmental and post-PNX signals enhances some aspects of compensatory lung growth and remodeling without altering its nonuniform spatial distribution.

Animals↗
PubMed2006

How much is there really? Why stereology is essential in lung morphometry.

Quantitative data on lung structure are essential to set up structure-function models for assessing the functional performance of the lung or to make statistically valid comparisons in experimental morphology, physiology, or pathology. The methods of choice for microscopy-based lung morphometry are those of stereology, the science of quantitative characterization of irregular three-dimensional objects on the basis of measurements made on two-dimensional sections. From a practical perspective, stereology is an assumption-free set of methods of unbiased sampling with geometric probes, based on a solid mathematical foundation. Here, we discuss the pitfalls of lung morphometry and present solutions, from specimen preparation to the sampling scheme in multiple stages, for obtaining unbiased estimates of morphometric parameters such as volumes, surfaces, lengths, and numbers. This is demonstrated on various examples. Stereological methods are accurate, efficient, simple, and transparent; the precision of the estimates depends on the size and distribution of the sample. For obtaining quantitative data on lung structure at all microscopic levels, state-of-the-art stereology is the gold standard.

Animals↗
PubMed2006

Splenectomy impairs diffusive oxygen transport in the lung of dogs.

The spleen acts as an erythrocyte reservoir in highly aerobic species such as the dog and horse. Sympathetic-mediated splenic contraction during exercise reversibly enhances convective O2 transport by increasing hematocrit, blood volume, and O2-carrying capacity. Based on theoretical interactions between erythrocytes and capillary membrane (Hsia CCW, Johnson RL Jr, and Shah D. J Appl Physiol 86: 1460-1467, 1999) and experimental findings in horses of a postsplenectomy reduction in peripheral O2-diffusing capacity (Wagner PD, Erickson BK, Kubo K, Hiraga A, Kai M, Yamaya Y, Richardson R, and Seaman J. Equine Vet J 18, Suppl: 82-89, 1995), we hypothesized that splenic contraction also augments diffusive O2 transport in the lung. Therefore, we have measured lung diffusing capacity (DL(CO)) and its components during exercise by a rebreathing technique in six adult foxhounds before and after splenectomy. Splenectomy eliminated exercise-induced polycythemia, associated with a 30% reduction in maximal O2 uptake. At any given pulmonary blood flow, DL(CO) was significantly lower after splenectomy owing to a lower membrane diffusing capacity, whereas pulmonary capillary blood volume changed variably; microvascular recruitment, indicated by the slope of the increase in DL(CO) with respect to pulmonary blood flow, was also reduced. We conclude that splenic contraction enhances both convective and diffusive O2 transport and provides another compensatory mechanism for maintaining alveolar O2 transport in the presence of restrictive lung disease or ambient hypoxia.

Animals↗
PubMed2006

Further examination of alveolar septal adaptation to left pneumonectomy in the adult lung.

Recent data from our laboratory are presented concerning alveolar septal adaptation following 42-45% lung resection by left pneumonectomy (PNX) in adult foxhounds compared to sham-operated control animals. Results confirm our previous conclusion that compensation in the remaining lung occurs without a net growth of additional alveolar septal tissue. The major ultrastructural responses are (a) alveolar capillary distention, which recruits capillary blood volume and surface area, leading to a 30-50% increase in lung diffusing capacity estimated by morphometry, a magnitude similar to that measured by physiologic methods; (b) a selectively increased volume of type 2 alveolar epithelial cells. These data, taken together with the balanced compensatory growth of alveolar septal cells observed in adult dogs following 55-58% lung resection by right PNX, support a graded alveolar cellular response to chronic mechanical strain with the alveolar epithelial cells being activated first; as strain increases further with greater lung resection other alveolar cells also become activated leading to an overt increase in septal tissue volume. The spatial distribution of lobar mechanical strain and lobar tissue volume assessed by high resolution computed tomography was markedly non-uniform after PNX, suggesting possible non-uniform distribution of alveolar cellular response. The sequential activation of physiologic recruitment and cellular adaptation confer additive functional benefits that optimize long-term exercise performance after PNX.

Acclimatization↗
PubMed2005

Regulated expression of hypoxia-inducible factors during postnatal and postpneumonectomy lung growth.

We previously found increased expression of erythropoietin receptor (EPO-R) in peripheral dog lung during postnatal and postpneumonectomy (PNX) lung growth. To study the upstream regulation of EPO-R, we analyzed the expression of hypoxia-inducible factors (HIF)-1alpha, -2alpha, and -3alpha during postnatal lung growth in immature and mature (2.5 and 12 mo old, respectively) dogs and during compensatory lung growth 3 wk and 10 mo after right PNX. Relative to their respective controls, HIF-1alpha transcript was 52-95% higher in immature lungs and 284% higher in the remaining lung 3 wk post-PNX. HIF-2alpha transcript did not change during maturation but was 42% lower 3 wk post-PNX. HIF-3alpha transcript was 53-65% lower in both the immature lung and 3 wk post-PNX. Changes were no longer detectable 10 mo post-PNX. No change in HIF transcripts was observed in kidney and liver post-PNX. Consistent with the mRNA changes, HIF-1alpha protein was 120 and 196% higher in growing lungs and 3 wk post-PNX relative to their respective controls. Overexpression of HIF-1alpha in cultured HEK-293 cells increased endogenous expression of EPO-R protein. These results demonstrate regulated expression of the HIF system and parallel changes in HIF-1alpha and EPO-R expression during two types of lung growth. Because the normal growing lung is not hypoxic, the HIF system likely responds to other signals encountered during sustained lung strain.

Aging↗
PubMed2005

Long-term enhancement of pulmonary gas exchange after high-altitude residence during maturation.

In a previous study, our laboratory showed that young dogs born at sea level (SL) and raised from 2.5 mo of age to beyond somatic maturity at a high altitude (HA) of 3,100 m show enhanced resting lung function (Johnson RL Jr, Cassidy SS, Grover RF, Schutte JE, and Epstein RH. J Appl Physiol 59: 1773-1782, 1985). To examine whether HA-induced adaptation improves pulmonary gas exchange during exercise and whether adaptation is reversible when animals return to SL before somatic maturity, we raised 2.5-mo-old foxhounds at HA (3,800 m) for 5 mo (to age 7.5 mo) before returning them to SL. Lung function was measured under anesthesia 1 mo and 2 yr after return to SL and during exercise approximately 1 yr after return. In animals exposed to HA relative to simultaneous litter-matched SL controls, resting circulating blood and erythrocyte volumes, lung volumes, septal volume estimated by a rebreathing technique, and lung tissue volume estimated by high-resolution computed tomography scan were persistently higher. Lung diffusing capacity, membrane diffusing capacity, and pulmonary capillary blood volume estimated at a given cardiac output were significantly higher in animals exposed to HA, whereas maximal oxygen uptake and hematocrit were similar between groups. We conclude that relatively short exposure to HA during somatic maturation improves long-term lung function into adulthood.

Acclimatization↗
PubMed2005

Lack of response to all-trans retinoic acid supplementation in adult dogs following left pneumonectomy.

We showed previously that removing 55-58% of the lung by right pneumonectomy (R-PNX) in adult dogs triggers compensatory growth of the remaining lung, but removing 42-45% of the lung by left PNX (L-PNX) does not. We also showed that, following R-PNX, supplemental all-trans retinoic acid (RA) selectively enhances alveolar capillary endothelial cell volume (Yan X, Bellotto DJ, Foster DJ, Johnson RL, Jr., Hagler HH, Estrera AS, and Hsia CC. J Appl Physiol 96: 1080-1089, 2004). We hypothesized that RA supplementation might enhance compensation following L-PNX and tested this hypothesis by administering RA (2 mg.kg(-1).day(-1), 4 days/wk) or placebo orally to litter-matched adult foxhounds for 4 mo following L-PNX. Resting lung function was measured under anesthesia. Air and tissue volumes of the remaining lung were assessed by high-resolution computed tomography scan and by detailed postmortem morphometric analysis of the fixed lung. There was no significant difference in resting lung function, lung volume, alveolar structure, or septal ultrastructure between RA and placebo treatment groups. We conclude that RA supplementation does not induce post-PNX compensatory lung growth in the absence of existing cellular growth activities initiated by other primary signals.

Adaptation, Physiological↗
PubMed2005

Enhanced alveolar growth and remodeling in Guinea pigs raised at high altitude.

To examine the effects of chronic high altitude (HA) exposure on lung structure during somatic maturation, we raised male weanling guinea pigs at HA (3800m) for 1, 3, or 6 months, while their respective male littermates were simultaneously raised at low altitude (LA, 1200m). Under anaesthesia, airway pressure was measured at different lung volumes. The right lung was fixed at a constant airway pressure for morphometric analysis under light and electron microscopy. In animals raised at HA for 1 month, lung volume, alveolar surface area and alveolar-capillary blood volume (V(c)) were elevated above LA control values. Following 3-6 months of HA exposure, increases in lung volume and alveolar surface area persisted while the initial increase in V(c) normalized. Additional adaptation occurred, including a higher epithelial cell volume, septal tissue volume and capillary surface area, a lower alveolar duct volume and lower harmonic mean diffusion barrier resulting in higher membrane and lung diffusing capacities. These data demonstrate enhanced alveolar septal growth and progressive acinar remodeling during chronic HA exposure with long-term augmentation of alveolar dimensions as well as functional compensation in lung compliance and diffusive gas transport.

Altitude↗
PubMed2005

A rebreathing method for measuring lung volume, diffusing capacity and cardiac output in conscious small animals.

We developed a multiple gas rebreathing technique for measuring lung diffusing capacity (DL(CO)), lung volume (V(L)) and cardiac output simultaneously in conscious spontaneously breathing small animals. Lung volume was measured from the dilution of methane (CH4) or sulfur hexafluoride (SF6) and verified independently by a helium washout technique. Cardiac output and DL(CO) were estimated from the uptake of acetylene and carbon monoxide, respectively. We tested guinea pigs at two levels of alveolar oxygen tension in order to estimate membrane diffusing capacity and pulmonary capillary blood volume by the Roughton-Forster technique. Results show that measured DL(CO) are consistent with reported values in anesthetized guinea pigs as well as with allometric comparison across species. Lung volume estimated from SF6 dilution agreed closely with that estimated independently from helium washout; however, lung volume estimated from CH4 dilution was systematically lower due to the addition of endogenously produced CH4 to the rebreathing system. We conclude that this technique can be used to measure resting lung function in conscious unsedated small animals.

Animals↗
PubMed2005

Ventilatory acclimatization in awake guinea pigs raised at high altitude.

To determine if laboratory strains of guinea pigs bred at sea level (SL) are "pre-adapted" to high altitude (HA), we raised litter-matched weanling Hartley guinea pigs for 4 months at SL, intermediate altitude (IA, 1250 m) or HA (3800 m) and exposed them acutely to 100, 21 and 12% inspired O2 at their respective altitude of residence. Control animals raised at SL were also exposed acutely to 10 and 8% inspired O2. In awake spontaneously breathing guinea pigs raised at SL, resting minute ventilation and tidal volume increased significantly when inspired O2 tension fell below about 60 mm Hg. In guinea pigs raised at IA or HA, ventilation was higher at any given inspired O2 tension in direct relationship to the altitude of residence. Resting hematocrit was also higher in animals raised at HA than at SL. We conclude that the pattern of ventilatory acclimatization to HA exposure in Hartley guinea pigs is similar to that in laboratory rats and human lowlanders; therefore laboratory guinea pigs are not pre-adapted and are suitable animals for the study of adaptation to high altitude.

Acclimatization↗
PubMed2005

The diabetic lung: relevance of alveolar microangiopathy for the use of inhaled insulin.

The alveolar-capillary network receives the entire cardiac output and constitutes the largest microvascular organ in the body, making it highly susceptible to systemic microangiopathy. Owing to its large reserves, symptoms and disability develop later in the lung than in smaller microvasculature such as the kidney or retina despite a comparable severity of anatomic involvement. Hence, pulmonary impairment in diabetes mellitus is under-recognized. Nonetheless, respiratory autonomic neuropathy and structural derangement of the thorax and lung parenchyma develop in many asymptomatic diabetic patients; the pathophysiology parallels that in other target organs. Even subclinical loss of alveolar microvascular reserves can be quantified noninvasively from lung diffusing capacity and its components (membrane diffusing capacity and alveolar-capillary blood volume) measured at a given cardiac output at rest or during exercise. The alveolar diffusion-perfusion relation tracks the recruitment of microvascular reserves in a manner independent of physical fitness. This article addresses the importance and pathophysiologic basis of diabetic pulmonary involvement, the assessment of diabetic alveolar microangiopathy, and the relevance of this understanding for the emerging use of inhaled insulin.

Administration, Inhalation↗
PubMed2004

Upregulation of erythropoietin receptor during postnatal and postpneumonectomy lung growth.

Circulating erythropoietin (EPO) stimulates erythrocytosis, whereas organ-specific local EPO receptor (EPOR) expression has been linked to angiogenesis, tissue growth, and development. On the basis of the observation of concurrent enhancement of lung growth and erythrocyte production during exposure to chronic hypoxia, we hypothesized that a paracrine EPO system is involved in mediating lung growth. We analyzed EPOR protein expression in normal dog lung tissue during postnatal maturation and during compensatory lung growth after right pneumonectomy (PNX). Membrane-bound EPOR was significantly more abundant in the immature lung compared with mature lung and in the remaining lung 3 wk after PNX compared with matched sham controls. COOH-terminal cytosolic EPOR peptides, which were even more abundant than membrane-bound EPOR, were also upregulated in immature lung but differentially processed after PNX. Apoptosis was enhanced during both types of lung growth in direct relationship to cellular proliferation and EPOR expression. We conclude that both developmental and compensatory lung growth involve paracrine EPO signaling with parallel upregulation but differential processing of EPOR.

Aging↗
PubMed2004

Regional lung growth following pneumonectomy assessed by computed tomography.

After pneumonectomy (PNX), mechanical strain on the remaining lung is greatly increased. To assess whether remaining lobes expand uniformly after left or right PNX (removing 42 and 58% of lung mass, respectively), we performed high-resolution computed tomography (CT) scans at 45 ml/kg above end-expiratory lung volume on adult male foxhounds after left or right PNX, which were compared with adult Sham controls. Air and tissue volumes were separately measured in each lobe. After left PNX, air and tissue volumes in the right upper and cardiac lobes increased approximately 2.2-fold above and below the heart, whereas volumes in right middle and lower lobes did not change significantly. After right PNX, air and tissue volumes in the left upper and middle lobes increased 2.3- to 2.7-fold across the midline anterior to the heart, whereas the left lower lobe expanded approximately 1.9-fold posterior to the heart. Regional changes in volume density of tissue post-PNX estimated by CT scan parallel postmortem estimates by morphometric analyses. Data indicate heterogeneous regional distribution of mechanical lung strain, which could influence the differential cellular compensatory response following right and left PNX.

Animals↗
PubMed2004

Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.

We measured diffusing capacities for carbon monoxide (DLCO) and nitric oxide, lung volume, and cardiac output by a rebreathing technique at two alveolar O2 tensions (PAO2) at rest and exercise. Membrane diffusing capacity for CO (DMCO) and VC were estimated from DLCO by the Roughton-Forster (RF) method and also from simultaneous lung diffusing capacity for NO and DLCO measured at one O2 tension (modified RF method). Estimates by these methods agreed closely in normal subjects (Tamhane et al., Chest 2001;120:1850-1856). Using these methods, we studied patients with stages II-III pulmonary sarcoidosis to determine (1) whether the modified RF method accurately estimates DMCO and VC in parenchymal disease and (2) whether sarcoidosis alters recruitment of diffusing capacity with respect to cardiac output. In patients, DMCO and VC estimated by the two methods agreed closely. DMCO was disproportionately reduced relative to VC at any given cardiac output, and the slope of the relationship between DLCO and cardiac output was moderately, though significantly, below normal. We conclude that in sarcoidosis (1) the modified RF method provides comparable estimates of DMCO and VC as the standard RF method and (2) the limitation to diffusive gas transport resides primarily in the membrane barrier, although recruitment of microvascular reserves is also modestly impaired.

Adult↗
PubMed2004

Lessons from a canine model of compensatory lung growth.

For over a century, canines have been used to study adaptation to surgical lung resection or pneumonectomy (PNX) that results in a quantifiable and reproducible loss of lung units. As reviewed by Schilling (1965), the first successful experimental pneumonectomies were performed in dogs and rabbits in 1881. By the early 1920s, it was appreciated that dogs can function normally with one remaining lung that increases in volume to fill the thoracic cavity (Andrus, 1923; Heuer and Andrus, 1922; Heuer and Dunn, 1920); these pioneering observations paved the way for surgeons to perform major lung resection in patients. Reports in the 1950s (Schilling et al., 1956) detail surprisingly well-preserved work performance in dogs following staged resection of up to 70% of lung mass. Since then, the bulk of the literature on post-PNX adaptation has shifted to rodents, especially for defining molecular mediators of compensatory lung growth. Because rodents are smaller and easier to handle, more animals can be studied over a shorter duration, resulting in time and cost savings. On the other hand, key aspects of lung anatomy, development, and time course of response in the rodent do not mimic those in the human subject, and few rodent studies have related structural adaptation to functional consequences. In larger mammals, anatomical lung development more closely resembles that in humans, and physiological function can be readily measured. Because dogs are natural athletes, functional limits of compensation can be characterized relatively easily by stressing oxygen transport at peak exercise. Thus, the canine model remains useful for relating structure to function, defining sources and limits of adaptation as well as evaluating therapeutic manipulation. This chapter summarizes key concepts of compensatory lung growth that have been consolidated from canine studies: (i) structure-function relationships during adaptation, (ii) dysanaptic (unequal) nature of compensation, and (iii) signals for initiation of cellular growth.

Animals↗
PubMed2004

Signals and mechanisms of compensatory lung growth.

Growth of the lung involves unique structure-function interactions not seen in solid organs. Mechanical feedback between the lung and thorax constitutes a major signal that sustains developmental as well as compensatory lung growth. After the loss of lung units as by pneumonectomy (PNX), increased mechanical stress and strain on the remaining units induce adaptive responses to augment oxygen transport, including 1) recruitment of alveolar-capillary reserves, 2) remodeling of existing tissue, and 3) regenerative growth of acinar tissue when strain exceeds a critical threshold. Alveolar hypoxia, hormones, and growth factors may feed into the mechanical feedback system to modify an existing growth response but are unlikely to initiate compensatory growth in the absence of sufficient mechanical signals. Whereas endogenous post-PNX alveolar growth preserves normal structure-function relationships, experimental manipulation of selected metabolic pathways can distort these relationships. Finally, PNX widens the disparity between the rapidly adapting acini and slowly adapting conducting airways and blood vessels, leading to disproportionate airflow and hemodynamic dysfunction and secondary hypertrophy of the right ventricle and respiratory muscles that limits overall organ function despite regeneration of gas exchange tissue. These are key concepts to consider when formulating approaches to stimulate or augment compensatory growth in chronic lung disease.

Adaptation, Physiological↗