Translating Basic Research Into Clinical Practice CHEST CHEST / 145 / 5 / MAY 2014 1121 journal.publications.chestnet.org A cute and chronic respiratory diseases represent major threats to human health. In this regard, a large-scale assessment of global disease burden identi- fied tobacco smoking and air pollution as two of the top three risk factors threatening global human health. 1 In normal homeostatic conditions, the respiratory mucosa, dendritic cells, and alveolar macrophages maintain a delicate balance by responding in an appropriate and timely manner to pathogenic microbes and air pol- lutants. Deficient mucosal inflammatory and immune responses to microorganisms may lead to lower respi- ratory tract infections and pneumonia. In contrast, exag- gerated or persistent responses of the bronchial and alveolar epithelium to environmental exposures may contribute to the pathogenesis of diverse pulmonary diseases, such as acute lung injury, pulmonary fibrosis, asthma, and COPD. Alveolar macrophages, dendritic cells, and bronchial epithelial cells are equipped with so-called “pattern recognition receptors” (PRRs) that Inflammasomes in Respiratory Disease From Bench to Bedside Guy G. Brusselle, MD, PhD; Sharen Provoost, PhD; Ken R. Bracke, PhD; Anna Kuchmiy, PhD; and Mohamed Lamkanfi, PhD The respiratory tract of human subjects is constantly exposed to harmful microbes and air pollutants. The immune system responds to these offenders to protect the host, but an unbalanced inflam- matory response itself may promote tissue damage and ultimately lead to acute and chronic respi- ratory diseases. Deregulated inflammasome activation is emerging as a key modulator of respiratory infections and pathologic airway inflammation in patients with asthma, COPD, and pulmonary fibrosis. Assembly of these intracellular danger sensors in cells of the respiratory mucosa and alveolar compartment triggers a proinflammatory cell death mode termed pyroptosis and leads to secretion of bioactive IL-1 b and IL-18. Here, we summarize and review the inflammasome and its downstream effectors as therapeutic targets for the treatment of respiratory diseases. CHEST 2014; 145 (5):1121–1133 Abbreviations: AIM2 5 absent in melanoma 2; ALR 5 absent in melanoma 2-like receptor; ASC 5 apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; ATP 5 adenosine-5 9-triphosphate; CS 5 ciga- rette smoke; NLR 5 nucleotide-binding oligomerization domain-like receptor; NLRC4 5 nucleotide-binding oligomeri- zation domain-like receptor, caspase activation and recruitment domain-containing 4; NLRP1b 5 nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b; NLRP3 5 nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3; OVA 5 ovalbumin; P2X 7 5 purinergic receptor; PRR 5 pattern recogni- tion receptor; ssRNA 5 single-stranded RNA; Th 5 T helper; TLR 5 Toll-like receptor Manuscript received August 13, 2013; revision accepted December 10, 2013. Affiliations: From the Laboratory for Translational Research of Obstructive Pulmonary Disease (Drs Brusselle, Provoost, and Bracke), Ghent University Hospital, Ghent, Belgium; the Depart- ments of Epidemiology and Respiratory Medicine (Dr Brusselle), Erasmus MC, Rotterdam, The Netherlands; the Department of Medical Protein Research (Drs Kuchmiy and Lamkanfi), Flanders Institute for Biotechnology (VIB), Ghent, Belgium; and the Depart- ment of Biochemistry (Drs Kuchmiy and Lamkanfi), Ghent Uni- versity, Ghent, Belgium. Funding/Support: Work in Dr Lamkanfi’s laboratory is supported in part by the European Union [Marie-Curie Grant 256432], Euro- pean Research Council [Grant 281600], and the Fund for Scientific Research Flanders (FWO) [Grants G030212N, 1.2.201.10.N.00, and 1.5.122.11.N.00]. Drs Provoost and Bracke are postdoctoral researchers of FWO. Presented work within the Department of Respiratory Medicine of Ghent University is funded by grants from the FWO, the Concerted Action of Ghent University, and the Interuniversity Attraction Poles Program. Correspondence to: Guy G. Brusselle, MD, PhD, Laboratory for Translational Research of Obstructive Pulmonary Disease, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium; e-mail: guy.brusselle@ugent.be © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1885 Downloaded From: http://journal.publications.chestnet.org/ by a Universitair Ziekenhuis Gent Kenniscentrum User on 09/24/2014