Involvement of type II pneumocytes in the pathogenesis of chronic obstructive pulmonary disease

Zhao, Chun-zhen; Fang, Xuekun; Wang, Diane; Tang, Fa-di; Wang, Xiangdong

doi:10.1016/j.rmed.2010.06.018

Cited by 47 publications

(33 citation statements)

References 51 publications

(49 reference statements)

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“…This observation is novel and extends our previous finding of reduced lung function and elevated COPD risk among 121ins2 heterozygous smokers [12]. Supporting an association between surfactant protein-B and COPD, type II pneumocytes have been proposed to play important roles in COPD development [29]. In line with this, surfactant protein-A [30] and surfactant protein-D [31,32] may be involved in smoking-related lung diseases, and cystic changes and paraseptal emphysema have been previously reported in interstitial lung disease associated with mutations in the surfactant protein-C gene [33,34].…”

Section: Discussionsupporting

confidence: 81%

Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

2012

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BackgroundMutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population.MethodsWe screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n = 10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study.ResultsIn the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV1 % predicted compared with noncarriers (t-test: p = 0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEV1 % predicted (p = 0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p = 0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and α1-antitrypsin ZZ homozygotes.ConclusionOur results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.

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Section: Discussionsupporting

confidence: 81%

Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

2012

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“…These cells stained positive for Mucin-1 (data not shown). Type II pneumocytes are proliferating epithelial cells that produce and secrete phospholipid surfactant (21,22). Like in the kidney, also in the lung the changes were apparent already at the age of 1.5 months (Fig.…”

Section: Resultsmentioning

confidence: 99%

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice

Herzig¹,

Kolly

Persohn

et al. 2011

Human Molecular Genetics

331

373

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD.

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“…The inflammatory cells, such as neutrophils, mast cells, macrophages, CD8 + T and B lymphocytes, are increased in number in the airway and lung parenchyma of COPD patients [23][24][25]. Type II alveolar epithelial cells may also contribute to the pathogenesis of COPD [26,27]. Various inflammatory cytokines, proteases and lung surfactant secreted by lung cells are all involved in the mechanism of COPD.…”

Section: Abstract: Interstitial Cells • Lung • Pathogenesis • Telocytmentioning

confidence: 99%

Potential significance of telocytes in the pathogenesis of lung diseases

Zheng

Bai

Wang³

2012

Expert Review of Respiratory Medicine

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Multiple cells play critical roles in the pathogenesis of lung diseases, even though the exact mechanisms are still not clear. Telocytes are characterized by telopodes, which are thin and long prolongations, and a small amount of cytoplasm rich with mitochondria, as shown by immune-positive staining against CD34, c-kit and vimentin. Telocytes have been found in many organs of mammals, including the trachea and lung. This report summarizes the latest findings associated with telocytes, with a special focus on the lung, and demonstrates that telocytes exist in the smooth muscle layer under cartilage and bronchiole in the lung, and also in the interstitial space of alveoli. Telocytes have a mediate connection with epithelial cells and direct connection with smooth muscle cells both in blood vessels and bronchiole in the lung. Telocytes also have a close relationship with other cell types, such as immune cells and stem cells. Telopodes appear with dichotomous branching and alternation of podom and podomer, forming a 3D network structure with complex homo- and hetero-cellular junctions. All characteristics of telocytes in lung tissue indicate that telocytes may play a potential, but important, role in the pathogenesis of lung diseases.

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Involvement of type II pneumocytes in the pathogenesis of chronic obstructive pulmonary disease

Cited by 47 publications

References 51 publications

Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice

Potential significance of telocytes in the pathogenesis of lung diseases

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