The role of IL‐6 and IL‐11 in hyperoxic injury in developing lung

Abstract

We examined the cytoprotective effect of interleukin-6 (IL-6) and interleukin-11 (IL-11) during oxidant injury in neonatal lung and the regulators of cell death in vitro and in vivo after oxidant exposure. Type II cells from day 21 fetal neonatal rat lungs were treated with varying concentrations of either IL-6 or IL-11 for 24 hr prior to exposure to H(2)O(2). Three-day-old transgenic lung-specific IL-11 and IL-6 overexpressing and wild type (WT) mouse pups were exposed to hyperoxia or room air for 3 days. Type II cells exposed to either IL-6 or IL-11 prior to oxidant injury exhibited improved survival compared to controls, 67% +/- 2.6 survivals in IL-6 pretreated cells compared to 48% +/- 1.6 in control; 63% +/- 3 survivals in IL-11 pretreated cells compared to 49% +/- 2.6 in control. The number of TUNEL positive cells in hyperoxia-exposed lungs was increased compared to room air animals (27 +/- 0.9 vs. 4 +/- 0.4; mean +/- SEM; P < 0.05). In contrast, the number of TUNEL positive cells was reduced in hyperoxia-exposed lungs from IL-11 (+) mice (15.2 +/- 2.2; mean +/- SEM; P < 0.05). There was an enhanced accumulation of Bcl-2 and reduction of Bax protein in hyperoxia-exposed IL-11 (+) compared to room air-exposed mice. This was not seen in hyperoxia-exposed IL-6 (+) pups. An increase in caspase-3 was seen in hyperoxia-exposed lungs of WT pups compared to IL-11 (+) pups. IL-11 and IL-6 provide protective effects against oxidant-mediated injury in fetal type II cells and IL-11 provides protection in vivo by down-regulation of caspase-mediated cell death.

Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

“…The role of IL-6 in neonatal lung injury, however, has been controversially discussed. While overexpression of IL-6 aggravated lung injury in newborn mice that were exposed to hyperoxia after birth, IL-6 overexpression provides protective effects against oxidant-mediated injury when mice are exposed to hyperoxia from day [28,29]. In contrast, the present study demonstrates that Il6 null mice exhibit a mild reduction of alveoli already under normoxia that could be related to reduced number of myofibroblasts and possibly impaired secondary septation.…”

Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice

“…We observed that mRNA of Ccl8 (MCP-2), Spp1 (osteopontin), Cxcl9 (Mig), IL1r2, Ccr5, Ccl24, and Itgam (CD11b, Mac-1) were increased and IL11 and Ccr7 were decreased by TiO 2 NPs. All these genes are probably relevant to the inflammation observed: Ccl8 is a well-known chemotactic agent for monocytes (32), Spp1 has a role in immune regulation and has Th1-cytokine functions (38), Cxcl9 is inducible in macrophages in response to interferon-␥ and may play a role in T cell trafficking (24), IL1r2 inhibits IL-1 activity by acting as a decoy target for IL-1 (11) (suggesting that its increase may be compensatory rather than contributory to pathology), Ccr5 is a receptor for MIP-1␣ and -1␤ and is known to have a role in lung inflammation (5), Ccl24 is strongly chemotactic for eosinophils (43), and Itgam is important in neutrophil recruitment to the lung (26), whereas IL-11 (9) and Ccr7 (13), which were decreased, are known to have a protective role in lung injury and inflammation. We also observed that protein amounts of multiple proinflammatory cytokines (e.g., eotaxin, G-CSF, IL-1␤, IL-2, IL-4, IP-10, M-CSF, MIP-1␣, MIP-1␤, MIP-2, TNF-␣) were increased with TiO 2 NP exposure, whereas VEGF was decreased.…”

Chorioamnionitis, Postnatal Factors and Proinflammatory Response in the Pathogenetic Sequence of Bronchopulmonary Dysplasia

“…Proinflammatory cytokines do not cross the placenta [66] . There is convincing experimental and clinical data which indicate that the profound proinflammatory cytokine response present in the airways and pulmonary tissue of preterm infants may reflect an inability to regulate inflammation through an adequate expression of the anti-inflammatory cytokines IL-4, IL-10, IL-11, IL-12, IL-13, IL-18 or IL-1 receptor antagonist [1,5,[67][68][69] . Cellular IL-10 mRNA was undetectable in most airway samples of preterm infants with BPD, but it was expressed in all term infants with respiratory failure [67] .…”