Distal Airspace Enlargement in the Fawn-Hooded Rat: Influences of Aging and Alveolar Wall Destruction

Morio, Yoshiteru; Matsushima, Masashi; Takahashi, Kazuhisa; Teramoto, Shinji; Oka, Teruaki; Fukuchi, Yoshinosuke

doi:10.1159/000050467

Cited by 7 publications

(7 citation statements)

References 22 publications

(30 reference statements)

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“…The Lm, which reflects average alveolar size including alveolar wall and lumen, was significantly larger in LEC than control rat lungs. These results are consistent with a previous report that FH rats, another strain of Ruby rats carrying a Rab38 deficiency, show distal air space enlargement accompanied by increased lung distensibility at an early age, which does not progress in an age-dependent manner (15).…”

Section: Resultssupporting

confidence: 93%

“…The lung involvement in HPS patients is characterized by usual interstitial pneumonia (UIP)-like interstitial pneumonia (16). However, rodent models of HPS develop hyperinflationary lungs (14,15,23) as seen in this study (Fig. 2) instead of fibrotic lungs, although its mechanism is not clarified yet.…”

Section: Discussionmentioning

confidence: 62%

“…Among them, FH rats have been investigated most frequently because of their interesting lung phenotype, i.e., pulmonary hypertension. Also, the morphological and functional study performed before the identification of Rab38 showed distal air space enlargement and increased lung distensibility without obvious alveolar destruction in FH rats, which occur at an early age and do not progress with age (15). However, no report on lung surfactant system has ever been available.…”

Section: Discussionmentioning

confidence: 99%

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Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

Osanai

Higuchi

Oikawa

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Several Long-Evans rat substrains carrying the phenotype of oculocutaneous albinism and bleeding diathesis are a rat model of Hermansky-Pudlak syndrome (HPS). The mutation responsible for the phenotype (Ruby) was identified as a point mutation in the initiation codon of Rab38 small GTPase that regulates intracellular vesicle transport. As patients with HPS often develop life-limiting interstitial pneumonia accompanied by abnormal morphology of alveolar type II cells, we investigated lung surfactant system in Long-Evans Cinnamon rats, one strain of the Ruby rats. The lungs showed conspicuous morphology of type II cells containing markedly enlarged lamellar bodies. Surfactant phosphatidylcholine and surfactant protein B were increased in lung tissues and lamellar bodies but not in alveolar lumen. Expression levels of mRNA for surfactant proteins A, B, C, and D were not altered. Isolated type II cells showed aberrant secretory pattern of newly synthesized [ 3 H]phosphatidylcholine, i.e., decreased basal secretion and remarkably amplified agonist-induced secretion.[ 3 H]phosphatidylcholine synthesis and uptake by type II cells were not altered. Thus Rab38-deficient type II cells appear to carry abnormality in lung surfactant secretion but not in synthesis or uptake. These results suggest that aberrant lung surfactant secretion may be involved in the pathogenesis of interstitial pneumonia in HPS.Ruby; Long-Evans Cinnamon rat; alveolar type II cells; lamellar body HERMANSKY-PUDLAK SYNDROME (HPS) is a rare autosomal recessive disorder resulting from abnormal trafficking relating to lysosome-related organelles such as melanosomes, platelet dense granules, and lamellar bodies in alveolar type II cells (10,29). HPS is clinically characterized by oculocutaneous albinism, bleeding diathesis, and, based on its genetic background, additional abnormalities such as progressive interstitial pneumonia. Interstitial pneumonia is the most serious complication arising in patients with HPS and has no effective therapy and is generally fatal by middle age. The lung histology show interstitial pneumonia characterized by enlarged alveolar type II cells that are fulfilled with giant lamellar bodies containing prominently increased surfactant phospholipids (16). It is possible that lung surfactant abnormalities may be closely related to lung pathology in HPS lungs.Several Long-Evans (LE) substrains including Fawn-hooded (FH) and Tester-Moriyama (TM) rats show oculocutaneous albinism and bleeding diathesis and hence are considered to be rat models of human HPS. The responsible gene Ruby was recently identified as Rab38 (18), a member of the Rab small GTPase family that regulates intracellular vesicle transport. A point mutation found in the initiation codon of Rab38 has been assumed to cause null translation of the protein. LE Cinnamon (LEC) rats, which carry ATP7B gene mutation and have been used as a rat model of Wilson disease (31), have also been identified as Ruby rats that harbor the Rab38 mutation (18). Thus Rab38 has been nominated...

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

Osanai

Higuchi

Oikawa

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Another clue to the origin of FHR-PAH is the known "hypoxia sensitivity" of FHR, meaning that they develop PAH and alveolar simplification in response to mild hypoxia. 11,16 Although FHR-PAH is reduced by supplemental oxygen, 16,17 it occurs despite normal PaO 2 , 11 suggesting a defect in the pulmonary vascular oxygen sensor. 18 The pulmonary circulation has a unique redox-based mitochondrial oxygen sensor.…”

Section: Clinical Perspective P 2641mentioning

confidence: 99%

An Abnormal Mitochondrial–Hypoxia Inducible Factor-1α–Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats

et al. 2006

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Background-The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain. Methods and Results-Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by Ϸ60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1␣), which then inhibited expression of oxygen-sensitive, voltage-gated K ϩ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H 2 O 2 ) or blocking HIF-1␣ activation (dominant-negative HIF-1␣) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3␣ (an HIF-1␣ repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1␣ activation; and reduced expression/activity of HIF-3␣, cytochrome c oxidase, and superoxide dismutase-2. Conclusions-FHRs

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“…Air space size normally increases with age, but this also varies with species. For example, guinea pigs (155) and rats (56,96) have a progressive increase in size until 12 and 18 mo [although there appears to be some differences between strains (56)], and hamsters attain maximum size by 6 wk (reviewed in Ref. 61).…”

Section: Comparative Anatomymentioning

confidence: 99%

Animal models of chronic obstructive pulmonary disease

Wright¹,

Cosio²,

Churg³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

371

326

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-The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role. chronic obstructive pulmonary disease CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is an increasingly important cause of morbidity and mortality. COPD is now the fifth leading cause of death worldwide (109), and recent estimates suggest that the prevalence is as high as 9 -10% of adults over age 40 (38, 131). In the developed world, cigarette smoking is by far the most important risk factor for COPD. Exposure to air pollution particles, occupational exposures to dusts and fumes (39), and, in the developing world, exposure to biomass fuels used for cooking is also believed to be etiological agents of COPD (38).There are few animal models of COPD related to air pollution particles, dusts and fumes, and biomass fuels; most COPD models have either used cigarette smoke or other approaches, including genetic modifications to mice, believed to reproduce some of the mechanisms behind cigarette smoke. We have recently reviewed mechanistic studies of smoke-exposed animal models (16). In this paper, we will focus on the pros and cons of different COPD animal models.The first question to ask in this context is what would constitute a perfect model of human COPD. This is not a simple question because human COPD consists of at least four anatomic lesions (further defined below): emphysema, small airway remodeling (including goblet cell metaplasia), chronic bronchitis, and pulmonary hypertension; a given patient may have any or all of these lesions. In addition, COPD patients may develop acute exacerbations that are believed to have an infectious basis. To further complicate matters, no matter which lesions are present, COPD develops and is slowly progressive over many years.Because COPD is closely related to the underlying anatomy of the lung, a good animal model should have pulmonary anatomy similar to that of humans. The fundamental mechanisms behind COPD should be similar in animal models and humans. The ideal model would allow the investigator to produce the various different anatomic lesions just listed, all in a short period of time. Unfortunately, all of the known animal models meet only some of the above criteria, and even another human would probably not meet all of them, because, as noted above, there is considerable human to human variation in th...

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Distal Airspace Enlargement in the Fawn-Hooded Rat: Influences of Aging and Alveolar Wall Destruction

Cited by 7 publications

References 22 publications

Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

An Abnormal Mitochondrial–Hypoxia Inducible Factor-1α–Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats

Animal models of chronic obstructive pulmonary disease

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