The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

Abstract

Rationale: Prolonged exposure to 100% O 2 causes hyperoxic acute lung injury (HALI), characterized by alveolar epithelial cell injury and death. We previously demonstrated that the murine chitinase-like protein, breast regression protein (BRP)-39 and its human homolog, YKL-40, inhibit cellular apoptosis. However, the regulation and roles of these molecules in hyperoxia have not been addressed. Objectives: We hypothesized that BRP-39 and YKL-40 (also called chitinase-3-like 1) play important roles in the pathogenesis of HALI. Methods: We characterized the regulation of BRP-39 during HALI and the responses induced by hyperoxia in wild-type mice, BRP-39-null (2/2) mice, and BRP-39 2/2 mice in which YKL-40 was overexpressed in respiratory epithelium. We also compared the levels of tracheal aspirate YKL-40 in premature newborns with respiratory failure. Measurements and MainResults: These studies demonstrate that hyperoxia inhibits BRP-39 in vivo in the murine lung and in vitro in epithelial cells. They also demonstrate that BRP-39 2/2 mice have exaggerated permeability, protein leak, oxidation, inflammatory, chemokine, and epithelial apoptosis responses, and experience premature death in 100% O 2 . Lastly, they demonstrate that YKL-40 ameliorates HALI, prolongs survival in 100% O 2 , and rescues the exaggerated injury response in BRP-39 2/2 animals. In accord with these findings, the levels of tracheal aspirate YKL-40 were lower in premature infants treated with hyperoxia for respiratory failure who subsequently experienced bronchopulmonary dysplasia or death compared with those that did not experience these complications.Conclusions: These studies demonstrate that hyperoxia inhibits BRP-39/YKL-40, and that BRP-39 and YKL-40 are critical regulators of oxidant injury, inflammation, and epithelial apoptosis in the murine and human lung.

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

“…Retention of GH 18 genes across species and evolutionary time has led to the belief that some of these moieties play essential roles in biology. Recent studies have confirmed this speculation (15,(18)(19)(20)(21), particularly for the prototypic CLP, chitinase 3-like-1 (CHI3L1; also called YKL-40 in humans and BRP-39 in mice). CHI3L1 has been shown by our laboratory and others to play major roles in anti-pathogen, antigen-induced, and oxidant-induced Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles.…”

Lung Diseases - Selected State of the Art Reviews

“…Initial studies in that area begin in the late 1970s and have started by looking at the combined effect of spasmogens on different measures of lung function in animals (45,46,57,99,102,112,131,152,180,181,192,208,209,224,244), as well as in humans (49,68,97,101,110,156,158,194,202,240). Apart from an interactive synergism at the level of ASM contraction, many other factors can account for these in vivo interactive synergisms.…”

“…in vivo ex vivo in vitro CCh (180) in sheep; HIST (112) in pigs Muscarinic agonists (ACh, MCh or CCh) HIST (158) in humans; HIST (131) and NE (33) in dogs HIST (71), and NE (87,185) in canine tracheal SM strips HIST MCh (158) and HIST (97) in humans MCh (131), ACh (33) and NE (12,33,131) …”

“…Similarly, if one uses a concentration just above the response threshold, the subsequent addition of a different or the same spasmogen will have more effect simply because it is now acting on the steeper part of the doseresponse curve. In fact, many of the previously documented examples of 'synergism' performed either in vivo (110,112,131,158,244) or ex vivo (38,71,87,135) were involving low concentrations of spasmogens, and were unable to demonstrate a synergism at higher concentrations for at least some of the reported spasmogenic interactions (71,87,131). So the level of basal tone, even if low, can seemingly synergize with the extrinsically delivered spamogen to cause AHR simply by an additive effect at the level of ASM activation Collectively, the force potentiation of one spasmogen (or baseline tone) on another spasmogen can be due to many factors such as: 1-use of sub-threshold or barely active concentrations of spasmogens, which simply act additively in terms of ASM activation but will be perceived as being synergistic in terms of ASM-force, ASM shortening, airway narrowing or airway resistance; 2-use of geometry-dependent measurements such as airway resistance; so that the effect of the second spasmogen is augmented by the reduced airway caliber caused by the first spasmogen; 3-a synergistic effect due to the contribution of vascular, neural or inflammatory effects when tested in vivo or in situ, which can be observed when the spasmogens used have vasoactive and inflammatory activities or when they can trigger either a vagal reflex and/or an increase in the efferent cholinergic traffic; and 4-a true synergistic effect on myosin cross-bridge cycling due to the convergence of intracellular signaling pathways that are activated by the ligation of two distinct GPCRs (such as Ca 2+ sensitization).…”

“…Chitinolytic activity has also been demonstrated in COPD patients 156,157 , as well as in models of cigarette smoke induced emphysema 157 . Interestingly, BRP39 gene deficient mice have increased epithelial cell apoptosis and alveolar destruction in response to cigarette smoke, but worsened pathology in hyperoxia-induced lung injury which is a more acute ARDS-like model 157,158 . Increased YKL40 has also been detected in the lungs and circulation of IPF patients, with levels correlating with survival 159,160 .…”