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IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.

Transforming growth factor (TGF)-␤ 1 has been implicated in the pathogenesis of fibrosis based upon its matrix-inducing effects on stromal cells in vitro, and studies demonstrating increased expression of total TGF-␤ 1 in fibrotic tissues from a variety of organs. The precise role in vivo of this cytokine in both its latent and active forms, however, remains unclear. Using replication-deficient adenovirus vectors to transfer the cDNA of porcine TGF-␤ 1 to rat lung, we have been able to study the effect of TGF-␤ 1 protein in the respiratory tract directly. We have demonstrated that transient overexpression of active, but not latent, TGF-␤ 1 resulted in prolonged and severe interstitial and pleural fibrosis characterized by extensive deposition of the extracellular matrix (ECM) proteins collagen, fibronectin, and elastin, and by emergence of cells with the myofibroblast phenotype. These results illustrate the role of TGF-␤ 1 and the importance of its activation in the pulmonary fibrotic process, and suggest that targeting active TGF-␤ 1 and steps involved in TGF-␤ 1 activation are likely to be valuable antifibrogenic therapeutic strategies. This new and versatile model of pulmonary fibrosis can be used to study such therapies. ( J. Clin. Invest.

Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

One of the oldest and most preserved of the The systemic response to tissue injury caused by infection or trauma is the well-recognized series of humoral and cellular reactions known collectively as the acute inflammatory response. This response consists of leukocytosis, fever, increased vascular permeability, alterations in plasma metal and steroid concentrations, along with increased levels of liver-derived plasma proteins (1, 2). The liver responds early to trauma with increased uptake of amino acids as well as iron and zinc. In addition, there is a marked increase in the hepatocyte mRNA for a number of plasma proteins. These include a1-acid glycoprotein, a1-proteinase inhibitor (a1-antitrypsin), a1-antichymotrypsin, haptoglobin, hemopexin, and fibrinogen in most species, along with C-reactive protein, C3, and factor B complement components and serum amyloid A protein in humans, and a2-macroglobulin and a1-cysteine proteinase inhibitor (major acute phase protein) in the rat. The change in mRNA is followed within a few hours by an increase in the secretion of the proteins by the liver and increased plasma levels of these acute phase reactants within 24 hr. The acute phase reaction has been the subject of recent reviews (3, 4). The identity of the putative hormone-like messenger, released at the site of injury and traveling to the liver, as suggested by Koj (5), has received considerable attention of late. It now appears certain that most nonhepatic acute phase reactions can be attributed to the release of a family of polypeptides, originally described as leukocyte endogenous mediator or endogenous pyrogen (6, 7), now known as interleukin 1 (IL-1), and a second series of peptides known as tumor necrosis factor (TNF). These polypeptide cytokines interact with a broad spectrum of target tissues and would appear to control major components of the inflammatory response (8, 9).Using in vitro hepatocyte cell cultures of primary rat hepatocytes and rat and human hepatoma cells, we and others have shown that IL-1 and TNF induce only a restricted acute phase response in vitro (10-15). The full hepatic acute phase protein response is controlled by a separate cytokine, originally described as fibrinogen-stimulating factor (16) and more recently known as hepatocyte-stimulating factor (HSF) (17-19). Human monocyte-derived HSF is a polypeptide released by activated monocytes and macrophages, which elutes from molecular sieve chromatography as a 25-to 30-kDa protein and has an isoelectric point of 5 (18,20,21). Human keratinocytes release HSFs with similar activities on hepatocytes (22). The cytokines IL-1 and TNF control only a subset of the acute phase protein genes (including a1-acid glycoprotein, C3, and haptoglobin) in human and rat hepatocytes while monocytic as well as keratinocytic HSF controls the expression of the remaining acute phase proteins (including the antiproteinases and fibrinogen) and has a lesser but still significant effect on the first subset of acute phase proteins (refs. 12 and 23; H.B., C.R.,...

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Fibrocytes are an indicator for disease activity of IPF and might be useful as a clinical marker for disease progression. This study suggests that quantification of circulating fibrocytes may allow prediction of early mortality in patients with IPF.

This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.