Oncostatin M Production by Blood and Alveolar Neutrophils during Acute Lung Injury

Abstract

SUMMARY:Polymorphonuclear neutrophils (PMN) are involved in the pathogenesis of acute lung injury (ALI), secreting numerous mediators such as proteases, reactive oxygen species, and cytokines. Because we had recently observed the ability of normal human PMN to degranulate and synthesize oncostatin M (OSM), an IL-6 -family cytokine, we quantified OSM production ex vivo by highly purified blood and alveolar PMN from 24 ventilated patients with ALI, including some patients with severe pneumonia. Most of the patients had no detectable OSM in plasma, and OSM production by cultured blood PMN was similar to that of healthy controls. However, OSM was present in bronchoalveolar lavage (BAL) fluid supernatant, with significantly higher levels during pneumonia. In addition, alveolar OSM levels correlated with the number of PMN obtained by BAL, suggesting that PMN are an important source of OSM within the alveoli. Indeed, purified alveolar PMN from all of the patients, especially those with pneumonia, strongly produced OSM. Interestingly, in the latter patients, alveolar PMN always produced more OSM than autologous blood PMN. These results document the functional duality of PMN in ALI by showing the participation of PMN in the modulation of lung inflammation. (Lab Invest 2001, 81:133-141).

Lipopolysaccharide Stimulates p38-dependent Induction of Antiviral Genes in Neutrophils Independently of Paracrine Factors

“…tin M. This gp130-activating ligand, associated with activation of Jak/STAT pathways, is also released from already synthesized pools (53). However, recombinant human oncostatin M failed to induce MX1 (data not shown).…”

FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins

“…In vivo, drug treatments, through killing of tumor cells, generate a local inflammatory reaction (Gadient and Patterson, 1999;Auernhammer and Melmed, 2000;Baumann and Gauldie, 1994;Wong and Wispe, 1997). The activated inflammatory cells deliver, in paracrine fashion, OSM, TNFa and IFNa/g to the surviving tumor cells (Grenier et al, 1999;Okamoto et al, 1997;Richards and Agro, 1994;Cameron and Churchill, 1980). The combination of drug and inflammatory cytokines then acts as a more potent cytotoxic effector, which in turn could be exploited to improve efficacy of anticancer drug treatments.…”

“…These cytokines are released at sites of injury by activated monocytes, neutrophils, mast cells, dentritic cells and lymphocytes (Gadient and Patterson, 1999;Auernhammer and Melmed, 2000;Grenier et al, 1999;Okamoto et al, 1997). The factors act in paracrine fashion on adjacent endothelial, epithelial and stromal cells, which in turn secrete their own set of mediators.…”

“…This increased responsiveness was observed despite the growth inhibition elicited by FR treatments alone (40%). Moreover, a strong potentiating effect was observed with the combination of FR and conditioned medium from LPS-activated lung macrophages, which are considered to be a biologically relevant source of inflammatory cytokines (Gadient and Patterson, 1999;Grenier et al, 1999;Okamoto et al, 1997;Cameron and Churchill, 1980). In contrast, no significant influence of LIF or IL-6 on DNA synthesis was detected, attesting to the differences (1) in FRdependent increase of cellular responsiveness to IL-6 cytokines and (2) in the signaling among these IL-6 cytokines that determines growth inhibition (Klausen et al, 2000;Douglas et al, 1997;Wang et al, 2000).…”

Differential Role of Neutrophils and Alveolar Macrophages in Hepatocyte Growth Factor Production in Pulmonary Fibrosis

“…Blood and BAL neutrophils were purified and cultured as previously described (Grenier et al, 2001). Briefly, 10 7 neutrophils/ml were cultured in the presence or absence of LPS (1 g/ml) for 20 hours in DMEM with 10% fetal bovine serum.…”