Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity.

Abstract

Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous α2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrin α7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrin α7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.

• Authors: Thai Tran, Chun Ming Teoh, John Kit Chung Tam, Yongkang Qiao, Chin Yein Chin, Oi Khuan Chong, Alastair G Stewart, Trudi Harris, Wai Shiu Fred Wong, Shou Ping Guan, Bernard P Leung, William T Gerthoffer, Helmut Unruh, Andrew J Halayko
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 10 Pg. 3991-4003 (Oct 2013) ISSN: 1530-6860 [Electronic] United States
• PMID: 23756649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bax protein, rat
• Biomarkers
• Integrins
• Laminin
• RNA, Small Interfering
• Thionucleotides
• bcl-2-Associated X Protein
• oblimersen
• Ovalbumin
• integrin alpha7beta1

Topics

• Animals
• Asthma (metabolism)
• Biomarkers
• Bronchial Hyperreactivity (metabolism)
• Cell Line
• Cell Survival
• Female
• Humans
• Integrins (genetics, metabolism)
• Laminin (metabolism, pharmacology)
• Mice
• Mice, Knockout
• Muscle Contraction (physiology)
• Muscle, Smooth (physiology)
• Ovalbumin (immunology)
• RNA, Small Interfering
• Signal Transduction (physiology)
• Thionucleotides (genetics, metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)