Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

Bartalesi, Barbara

doi:10.1183/09031936.04.00067204

Cited by 152 publications

(129 citation statements)

References 27 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…Consistent with previous observations (14,15), C57BL/6 WT mice displayed marked increases in lung airspace after 12-wk CS exposure relative to air-treated controls, as determined by comparative histologic examination (Fig. S1) and mean linear intercept (MLI) measurements (Fig.…”

Section: Resultssupporting

confidence: 76%

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Chen

Lam

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

351

357

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B −/− mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1 −/− mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

show abstract

Section: Resultssupporting

confidence: 76%

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Chen

Lam

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

351

357

View full text Add to dashboard Cite

show abstract

“…The clinical significance of our work is related to the finding of increased apoptosis of alveolar epithelial and endothelial cells in the lungs of COPD patients who smoke cigarettes and in animal models of emphysema (26,(30)(31)(32). Our data suggest that the effect of cigarette smoking on the A1AT antiapoptotic function is reversible and may be linked to the turnover of the protein as it is synthesized from the liver or to the restoration of native A1AT by reduction of the oxidized protein.…”

Section: Discussionmentioning

confidence: 79%

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Lockett

Demark

et al. 2012

Mol Med

View full text Add to dashboard Cite

α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.

show abstract

“…TNF-a R2 may be involved in the failure of weight gain in CS-exposed mice, since the current authors observed similar increases in weight in air-and CS-exposed TNF-a R2 KO mice, while a failure of weight gain was observed in WT and TNF-a R1 KO mice exposed to smoke. It is obvious that the smaller increases in weight in WT and TNF-a R1 KO mice were already visible in the first few weeks, while no emphysema has been observed following exposure to CS for 1 month (current authors' observations and [47]). In contrast to humans where weight loss, which occurrs in a subgroup of patients who develop severe COPD and emphysema, is a late phenomenon related to systemic effects of the disease, the early alterations of body weight in this mouse model of COPD seem to be due to an acute effect of cigarette smoking.…”

Section: Ai D'hulst Et Al Tnf-a R2 and Smoke-induced Emphysemamentioning

confidence: 91%

Role of tumour necrosis factor-α receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema

D’hulst

Bracke²,

Maes³

et al. 2006

Eur Respir J

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-a has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-a receptors.To investigate the contribution of each TNF-a receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-a R1 knockout (KO) mice, TNF-a R2 KO mice and wild type (WT) mice.CS was found to significantly increase the protein levels of soluble TNF-a R1 (by four-fold) and TNFa R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-a R1 KO mice. In TNF-a R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CSexposed TNF-a R2 KO mice in contrast to WT and TNF-a R1 KO mice. CS-exposed WT and TNF-a R1 KO mice failed to gain weight, whereas the body mass of TNF-a R2 KO mice was not affected.These current findings suggest that both tumour necrosis factor-a receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-a receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.

show abstract

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

Cited by 152 publications

References 27 publications

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Role of tumour necrosis factor-α receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema

Contact Info

Product

Resources

About