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Are Acute Exacerbations Driven by Cellular Mechanisms?
Acute Exacerbations of IPF (AE-IPF) are defined as “acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF.”1 Patients with IPF may experience acute exacerbations at any time during the course of their disease, and there is no link to the level of pulmonary function derangement.1 AE-IPF are associated with a very poor prognosis. Among 461 patients with IPF examined retrospectively, the median survival from onset of AE-IPF was just 2.2 months, and 50% of patients expired while in the hospital.2
The pathomechanisms of AE-IPF are not well understood, and this is an area of active investigation.3 Whether AE-IPFs are an externally induced, incidental occurrence or a result of underlying cellular mechanisms is an area of active debate.4 Building upon prior research, Schupp, Binder, Jäger, Cillis, et al sought to determine the role of macrophage activation in AE-IPF.5
What They Did
Over a period of 7 years, the authors conducted standardized bronchoscopy with bronchoalveolar lavage (BAL) on 71 patients with IPF, with and without AE-IPF, as well as on 20 healthy volunteers.5 BAL was evaluated for differential cell counts and cell cytokine profiles. Specifically, chemokines produced by classically activated (ie, M1) macrophages (IL-1β, TNF-α, CXCL1, IL-8) and by alternatively activated (ie, M2) macrophages (CCL2, CCL17, CCL18, CCL22, IL-1ra) were evaluated.
What They Found
The percentage of BAL neutrophils was significantly increased in patients with AE-IPF compared with stable patients.5 Further, the production rate of the proinflammatory cytokines CXCL1 and IL-8 was increased along with cytokines produced by alternatively activated macrophages (CCL2, CCL17, CCL18, CCL22, and IL-1ra). Seven patients who experienced AE-IPF had serial lavages obtained. During AE-IPF, CCL18 production was significantly increased, and there was a significant increase of neutrophils from 5.8% to 18.0%. Additionally, high baseline levels of CCL18 production by BAL cells were significantly associated with the occurrence of AE-IPF in the future.
What It Means
During AE-IPF, BAL cell cytokine production levels demonstrate both upregulation of proinflammatory as well as anti-inflammatory/M2 cytokines.5 These data appear to indicate that AE-IPF are driven by cellular mechanisms including M2 macrophage activation and are not incidental events.
Link to Abstract: http://www.ncbi.nlm.nih.gov/pubmed/?term=25590613
- Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176:636-643.
- Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37:356-363.
- Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J. 2007;30:835-839.
- Johannson KA, Vittinghoff E, Lee K, et al. Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J. 2014;43:1124-1131.
- Schupp JC, Binder H, Jager B, et al. Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis. PLoS One. 2015;10:e0116775.