Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion
Gui-Lan Chen, … , Jin Zhang, Bo Zeng
Gui-Lan Chen, … , Jin Zhang, Bo Zeng
Published December 21, 2023
Citation Information: J Clin Invest. 2024;134(5):e174508. https://doi.org/10.1172/JCI174508.
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Research Article Pulmonology

Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion

Abstract

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure in mice due to a deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of the lamellar body (LB), a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated the release of surfactant and ATP from LBs fused with the plasma membrane. The released ATP evoked Ca2+ signaling in AT2 cells and potentiated exocytic fusion of more LBs. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels in preparing the lungs for the first breath at birth and maintaining respiration throughout life.

Authors

Gui-Lan Chen, Jing-Yi Li, Xin Chen, Jia-Wei Liu, Qian Zhang, Jie-Yu Liu, Jing Wen, Na Wang, Ming Lei, Jun-Peng Wei, Li Yi, Jia-Jia Li, Yu-Peng Ling, He-Qiang Yi, Zhenying Hu, Jingjing Duan, Jin Zhang, Bo Zeng

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Figure 4

Lethal pulmonary phenotypes of Tmem63a/b-KO mice.

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Lethal pulmonary phenotypes of Tmem63a/b-KO mice. (A) Survival curves fo...
(A) Survival curves for constitutive Tmem63a/b-KO mice of different genotypes. The numbers of mice are shown in parentheses. (B) Failure of alveolar expansion in Tmem63b-KO mice after birth (P0). Original magnification, ×2. (C) Survival curves of AEC-specific Tmem63a/b conditional-KO mice with different genotypes. Aqp5-Cre was expressed in AT1 cells and approximately 50% of AT2 cells SPC-Cre was expressed in all AT2 cells. (D) Survival curves for tamoxifen-inducible, AEC-specific Tmem63a/b-cDKO mice. Ager-CreERT2 was expressed in AT1 cells and approximately 10% of AT2 cells; Nkx2.1-CreERT2 was expressed in AT1 cells and approximately 80% of AT2 cells; and Sftpc-CreERT2 was expressed in all AT2 cells. Ctrl-63ab represents 63afl/fl 63bfl/fl mice without Cre, and others are with the corresponding CreERT2. (E) Micro-CT images of mouse lungs after tamoxifen induction. Arrows indicate regions of atelectasis. (F) Mean lung volume intensities for mice before and after tamoxifen induction, measured from the micro-CT images. n = 3 mice. (G) Atelectasis in cDKO mice illustrated by freshly dissected lungs and H&E-stained sections. Arrows indicate collapsed lobes. Scale bars: 200 μm. (H) A dramatic decline of SpO2 before respiratory failure was observed in cDKO mice. n = 3 mice. (I) Characteristics of pulmonary edema in cDKO mice at post-tamoxifen day 12. n = 5, 9, and 7 mice for lung weight from left to right; n = 3 mice for wet/dry ratio. (J) Body weights in cDKO mice at post-tamoxifen day 12. n = 5, 9, and 7 mice from left to right. (K) Deficiency of secreted SPC, surfactant phospholipid DPPC, and ATP in BALF collected from cDKO mice at post-tamoxifen day 10. n = 3, 5, and 3 mice from left to right in each graph. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Tukey’s test.