Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease

Abstract

SUMMARY The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally-derived chitin polymers in the airways and expression of pro-fibrotic cytokines. Over time, these mice develop spontaneous pulmonary fibrosis, which is ameliorated by restoration of lung chitinase activity by genetic or therapeutic approaches. AMCase-deficient epithelial cells express fibrosis-associated gene sets linked with cell stress pathways. Mice with lung fibrosis due to telomere dysfunction and humans with interstitial lung disease also accumulate excess chitin polymers in their airways. These data suggest that altered chitin clearance could exacerbate fibrogenic pathways in the setting of lung diseases characterized by epithelial cell dysfunction.

The fungal ligand chitin directly binds TLR 2 and triggers inflammation dependent on oligomer size

“…C10-15 clearly elicited fulminant local immune cells infiltration indicated by a rapid and strong increase in local EGFP fluorescence (Fig 1F and G). Next, C10-15 oligomers were also administered intratracheally to assess lung inflammation [9]. Consistent with [19] showing an influx of neutrophils into the lung within 6 h of crude chitin treatment, C10-15 led to a significant influx of neutrophils in BALF ( Fig 1H) and lung tissue ( Fig 1I).…”

“…From a translational perspective, our study raises the possibility that chitin oligomers could serve as tools for developing therapies in chitin-mediated inflammatory disease conditions, such as fungal-or house-dust mite-related asthma and lung fibrosis [9]. Efforts in the latter area could now center on chitin-TLR2 binding and activation as key patho-biological events, and on developing biologicals (e.g., SSL3-derivatives or blocking antibodies), short chitin oligomers, or other "chito-mimetic" TLR2 antagonists structurally resembling short-chain NAGs to block these steps.…”

Lung epithelium: barrier immunity to inhaled fungi and driver of fungal-associated allergic asthma

“…Moreover, the response to chitin is fully abrogated in the triple knockout, thus each of these epithelial cytokines have a partially redundant role in controlling allergic inflammation [32]. Chitin availability in the airway lumen is also regulated by a chitinolytic enzyme acidic mammalian chitinase, which is constitutively secreted by epithelial cells [33]. Thus, epithelial cells are now widely believed to be a major sensor and responder to chitin exposure in the lungs.…”

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

“…4 With this approach, ageing, smoking, environmental exposures (eg, accumulation of environmental chitin 59 ), and genetic background are predisposing risk factors. 60,61 Epidemio logical studies confirm IPF as a disease of ageing, with interstitial lung abnormalities becoming increasingly prevalent with advancing age.…”