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Rationale: Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis., Objectives: We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis., Methods: We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography., Measurements and Main Results: Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P ≤ 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable-adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001)., Conclusions: Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis.

Rationale: Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy., Objectives: Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis., Methods: Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days., Measurements and Main Results: Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial-mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK(-/-) mice., Conclusions: Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury., Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury., Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined., Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC., Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

Pulmonary hypertension (PH) can develop in lung fibrosis, and contributes to increased morbidity and mortality. Noninvasive parameters in the evaluation of PH in lung disease could aid in the management of these subjects. In this study, we aimed to characterize the role of brain natriuretic peptide (BNP) and the six-minute walk distance (6-MWD) in the assessment of pulmonary hypertension (PH) in subjects with lung fibrosis. Subjects with lung fibrosis and elevated BNP levels (n = 20) had significantly more severe PH during right heart catheterization than those with lung fibrosis, and normal BNP levels (mean pulmonary arterial pressure (40.85 +/- 3.2 mm Hg vs. 23.42+/-1.44 mm Hg, respectively) (n = 19) (p < 0.001). Significant correlations between lung volumes and BNP concentrations were not observed. A weak correlation existed between capillary pO(2) and 6-MWD (r = 0.42; p < 0.001). The presence of moderate-severe PH was associated with significant reduction of the 6-MWD. BNP concentrations predicted moderate-severe PH with 100% sensitivity and high specificity (89%). We conclude that BNP is an excellent marker for the presence of PH in patients with lung fibrosis. In addition, our data suggest that PH contributes significantly to exercise limitation in patients with severe lung fibrosis, raising the possibility that treatment of PH may be beneficial in these patients.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease of unknown etiology. For optimal therapeutic management of IPF an accurate tool is required for discrimination between reversible and irreversible types of the disease. However, such noninvasive tools are few, and even with high-resolution computed tomography (HRCT), which is the most trusted method for doing so, the nature of the disease activity in IPF cannot always be accurately predicted. The aims of the present study were to assess the values of surfactant protein (SP)-A and SP-D in semiquantifying the extent of disease in IPF and in predicting deterioration in restrictive pulmonary function and survival over a follow-up period of 3-yr. SP-A and SP-D in sera were measured with enzyme-linked immunosorbent assays as previously described. Fifty-two IPF patients were studied to evaluate the association between serum SP-A and SP-D and disease extent on HRCT, deterioration in pulmonary function, and survival during 3 yr of follow-up. Both SP-A and SP-D concentrations were significantly correlated with the extent of alveolitis (a reversible change), whereas they did not correlate with the progression of fibrosis (an irreversible change). The SP-D concentration, unlike that of SP-A, was also related to the extent of parenchymal collapse and the rate of deterioration per year in pulmonary function. The concentrations of SP-A and SP-D in patients who died within 3 yr were significantly higher than in patients who were still alive after 3 yr. We propose that assays of SP-A and SP-D in sera from IPF patients are useful tools for understanding some pathologic characteristics of the disease, that SP-D may be a good predictive indicator of the rate of decline in pulmonary function, and that a combination of the assays for SP-A and SP-D may be helpful in predicting the outcome of patients with IPF.

It has been shown that interleukin 8 (IL-8) is increased in bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF) and there is increasing evidence that it is involved in the pathogenesis of this disease. To date, no data are available as to whether IL-8 is elevated in sera of IPF patients. We obtained sera from 42 patients with IPF and 20 healthy controls at time of BAL. From 20 of 42 patients with IPF and 12 of 20 controls BALF was available, enabling us to measure IL-8 in serum and BALF of the same time point. IL-8 was significantly elevated in serum (54.7 +/- 7.5 pg/ml, p < 0.0001) and BALF (715.7 +/- 112.4 pg/ml, p < 0.0001) of patients with IPF compared with controls (IL-8 in serum, 5.2 +/- 0.8 pg/ml; IL-8 in BALF, 67.3 +/- 9.7 pg/ml). We observed a significant positive correlation between IL-8 levels in BALF and percentage of BALF neutrophils (p < 0.001) and between serum IL-8 and BALF IL-8 levels (p < 0.005) in patients with IPF. Consequently, the serum IL-8 level correlated positively with the percentage of BAL neutrophils (p < 0.01), indicating that it may reflect the degree of neutrophilic alveolitis in IPF. Furthermore, the serum IL-8 level showed a negative correlation with important indicators of impairment of lung function (DL(CO), TLC, VC) and PaO2. In conclusion, we were able to demonstrate that the degree of neutrophilic alveolitis in IPF is reflected by increased serum levels of IL-8 and we suggest that the serological assessment of IL-8 may provide a useful parameter for clinicians in monitoring patients with IPF.

Serum levels of free radical activity were measured in 37 patients with idiopathic pulmonary fibrosis (IPF) and 16 control subjects. Three assays used were (1) simultaneously measured levels of the 9,11-diene conjugate of linoleic acid and 9,12-linoleic acid expressed as a percent molar ratio (%MR), a measure of free-radical-mediated lipid peroxidation; (2) thiobarbituric acid reactive substances (TBARS), one of which is malondialdehyde; (3) desferrioxamine-chelatable iron assay, a measure of the potential iron available to catalyze free radical generation. Mean %MR, TBARS and desferrioxamine-chelatable iron were all elevated initially in patients with IPF compared with control subjects (%MR, p < 0.0001; TBARS, p = 0.0013; desferrioxamine-chelatable iron, p = 0.0029). Furthermore, the serum %MR was higher in a subset of patients with clinically worsening IPF than in those patients with clinically stable disease (p = 0.002). Treatment did not appear to affect the three different serum indicators of free radical activity. Thus, lipid peroxidation appears to be increased in patients with IPF and is associated with an increase in desferrioxamine-chelatable iron levels. Serum % MR levels appeared to correlate with clinical disease activity, and they may have a role in monitoring disease activity.