Regulation of macroautophagy in amiodarone induced pulmonary fibrosis

Mahavadi, Poornima; Henneke, Ingrid; Knudsen, Lars; Ruppert, Clemens; Venkatesan, Shalini; Liebisch, Gerhard; Chambers, Rachel C.; Piskulak, K; Ochs, Matthias; Schmitz, G.; Vancheri, Carlo; Seeger, Werner; Korfei, Martina; Güenther, Andreas

doi:10.1055/s-0033-1363111

Cited by 1 publication

(5 citation statements)

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“…Because immunogold labeling demonstrated a preferential binding of LC3B antibodies to the limiting membrane of lamellar bodies in our previous studies (10,25), we closely examined the ultrastructure of AECII in LC3B 2/2 mice. The morphology of lamellar bodies with respect to the densely packed lipid layers as well as the limiting membrane did not differ between WT and LC3B 2/2 mice.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, giant lamellar bodies, alterations in the surfactant secretion pathway, and lysosomal stress were linked to the development of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS)-associated and in amiodarone-induced lung fibrosis (12,13). Along the same lines, we and others have shown that autophagy, a lysosome-dependent protein quality control mechanism of a cell, is either defective as in IPF and in HPS-associated lung fibrosis or excessively active as in the amiodarone model (10,(14)(15)(16), which, in either case, indicates the pathologic relevance of autophagy in the development of lung fibrosis.…”

mentioning

confidence: 80%

“…Each group consisted of about 5-10 animals: LC3B 2/2 or WT mice. Mice were euthanized according to the protocols previously described (10,13). Shock-frozen lung tissue samples from 16 patients with IPF (mean age 54 6 SD: 9.14) and 6 nondiseased control subjects (donors; mean age 48.16 6 SD: 8) were used for homogenization and subsequent Western blot analysis.…”

Section: Mice and Human Lung Tissuementioning

confidence: 99%

“…Likewise, alterations in the lysosomal compartment within the AECII in both clinical as well as experimental models of lung fibrosis are well documented. Firstly, pronounced changes in surfactant properties in patients with IPF have been reported (7)(8)(9)(10)(11). Furthermore, giant lamellar bodies, alterations in the surfactant secretion pathway, and lysosomal stress were linked to the development of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS)-associated and in amiodarone-induced lung fibrosis (12,13).…”

mentioning

confidence: 99%

“…We previously demonstrated that LC3B is localized to the limiting membrane of lamellar bodies of AECII in 2 models of lung fibrosis: the amiodarone model and the HPS model (10,16). In addition, in the amiodarone model, we reported that the autophagosomes and lamellar bodies share the same membrane (16) and under conditions of HPS1 knockdown, overexpression of LC3B rescued cells from defective autophagy (10). Based on these observations, we now aimed to further understand the role of LC3B in the development of lung fibrosis.…”

mentioning

confidence: 99%

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Susceptibility of microtubule‐associated protein 1 light chain 3β (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis

Kesireddy¹,

Chillappagari

Ahuja³

et al. 2019

The FASEB Journal

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Insufficient autophagy has been reported in idiopathic pulmonary fibrosis (IPF) lungs. Specific roles of autophagy‐related proteins in lung fibrosis development remain largely unknown. Here, we investigated the role of autophagy marker protein microtubule‐associated protein 1 light chain 3β (LC3B) in the development of lung fibrosis. LC3B–/– mice upon aging show smaller lamellar body profiles, increased cellularity, alveolar epithelial cell type II (AECII) apoptosis, surfactant alterations, and lysosomal and endoplasmic reticulum stress. Autophagosomal soluble N‐ethylmaleimide–sensitive factor attachment protein receptor syntaxin 17 is increased in the AECII of aged LC3B–/– mice and patients with IPF. Proteasomal activity, however, remained unaltered in LC3B–/– mice. In vitro knockdown of LC3B sensitized mouse lung epithelial cells to bleomycin‐induced apoptosis, but its overexpression was protective. In vivo, LC3B–/– mice displayed increased susceptibility to bleomycin‐induced lung injury and fibrosis. We identified cathepsin A as a novel LC3B binding partner and its overexpression in vitro drives MLE12 cells to apoptosis. Additionally, cathepsin A is increased in the AECII of aged LC3B–/– mice and in the lungs of patients with IPF. Our study reveals that LC3B mediated autophagy plays essential roles in AECII by modulating the functions of proteins like cathepsin A and protects alveolar epithelial cells from apoptosis and subsequent lung injury and fibrosis.—Kesireddy, V. S., Chillappagari, S., Ahuja, S., Knudsen, L., Henneke, I., Graumann, J., Meiners, S., Ochs, M., Ruppert, C., Korfei, M., Seeger, W., Mahavadi, P. Susceptibility of microtubule‐associated protein 1 light chain 3β (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis. FASEB J. 33, 12392–12408 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%