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1.  Cytoplasmic motions, rheology, and structure probed by a novel magnetic particle method 
The Journal of Cell Biology  1985;101(1):130-140.
The motions of magnetic particles contained within organelles of living cells were followed by measuring magnetic fields generated by the particles. The alignment of particles was sensed magnetometrically and was manipulated by external fields, allowing non-invasive detection of particle motion as well as examination of cytoplasmic viscoelasticity. Motility and rheology data are presented for pulmonary macrophages isolated from lungs of hamsters 1 d after the animals had breathed airborne gamma-Fe2O3 particles. The magnetic directions of particles within phagosomes and secondary lysosomes were aligned, and the weak magnetic field produced by the particles was recorded. For dead cells, this remanent field was constant, but for viable macrophages, the remanent field decreased rapidly so that only 42% of its initial magnitude remained 5 min after alignment. A twisting field was applied perpendicular to the direction of alignment and the rate at which particles reoriented to this new direction was followed. The same twisting was repeated for particles suspended in a series of viscosity standards. Based on this approach, the low-shear apparent intracellular viscosity was estimated to be 1.2-2.7 X 10(3) Pa.s (1.2-2.7 X 10(4) poise). Time-lapse video microscopy confirmed the alignment of ingested particles upon magnetization and showed persistent cellular motility during randomization of alignment. Cytochalasin D and low temperature both reduced cytoplasmic activity and remanent-field decay, but affected rheology differently. Magnetic particles were observed in association with the microtubule organizing center by immunofluorescence microscopy; magnetization did not affect microtubule distribution. However, both vimentin intermediate filaments and f-actin reorganized after magnetization. These data demonstrate that magnetometry of isolated phagocytic cells can probe organelle movements, rheology, and physical properties of the cytoskeleton in living cells.
PMCID: PMC2113644  PMID: 4040136
2.  Effects of rock wool on the lungs evaluated by magnetometry and biopersistence test 
Asbestos has been reported to cause pulmonary fibrosis, and its use has been banned all over the world. The related industries are facing an urgent need to develop a safer fibrous substance. Rock wool (RW), a kind of asbestos substitute, is widely used in the construction industry. In order to evaluate the safety of RW, we performed a nose-only inhalation exposure study in rats. After one-month observation period, the potential of RW fibers to cause pulmonary toxicity was evaluated based on lung magnetometry findings, pulmonary biopersistence, and pneumopathology.
Using the nose-only inhalation exposure system, 6 male Fischer 344 rats (6 to 10 weeks old) were exposed to RW fibers at a target fiber concentration of 100 fibers/cm3 (length [L] > 20 μm) for 6 hours daily, for 5 consecutive days. As a magnetometric indicator, 3 mg of triiron tetraoxide suspended in 0.2 mL of physiological saline was intratracheally administered after RW exposure to these rats and 6 unexposed rats (controls). During one second magnetization in 50 mT external magnetic field, all magnetic particles were aligned, and immediately afterwards the strength of their remanent magnetic field in the rat lungs was measured in both groups. Magnetization and measurement of the decay (relaxation) of this remanent magnetic field was performed over 40 minutes on 1, 3, 14, and 28 days after RW exposure, and reflected cytoskeleton dependent intracellular transport within macrophages in the lung. Similarly, 24 and 12 male Fisher 344-rats were used for biopersistence test and pathologic evaluation, respectively.
In the lung magnetometric evaluation, biopersistence test and pathological evaluation, the arithmetic mean value of the total fiber concentration was 650.2, 344.7 and 390.7 fibers/cm3, respectively, and 156.6, 93.1 and 95.0 fibers/cm3 for fibers with L > 20 μm, respectively. The lung magnetometric evaluation revealed that impaired relaxation indicating cytoskeletal toxicity did not occur in the RW exposure group. In addition, clearance of the magnetic tracer particles was not significantly affected by the RW exposure. No effects on lung pathology were noted after RW exposure.
These findings indicate that RW exposure is unlikely to cause pulmonary toxicity within four weeks period. Lung magnetometry studies involving long-term exposure and observation will be necessary to ensure the safety of RW.
PMCID: PMC2670311  PMID: 19323845
3.  Diminished organelle motion in murine Kupffer cells during the erythrocytic stage of malaria 
Parasitized erythrocytes are ingested by murine hepatic macrophages during malaria infection. We non-invasively monitored how this altered the motion of intracellular phagosomes in Kupffer cells using magnetometry. Submicrometric γFe2O3 particles were injected prior to malaria infection. They were cleared from the blood, primarily by Kupffer cells, and retained within their phagosomes. The mice were periodically magnetized. After removing this external magnet, the aligned iron particles created a remnant magnetic field (RMF) which then decayed (relaxation), reflecting the motion of particle-containing phagosomes. After baseline measurements of relaxation, the mice were injected intravenously with Plasmodium chabaudi-parasitized or normal murine red blood cells (RBCs). During the next 15 days, relaxation measurements, parasitaemia and haematocrit values were monitored. At 6 days post injection with 3 × 107 parasitized RBCs, relaxation rates had decreased. At this time, all mice had parasitaemias greater than 58 per cent and haematocrits less than 20 per cent. At day 7, while the parasitaemias were declining, the rate of relaxation continued to decrease. Throughout the experiment, relaxation remained constant in animals injected with normal RBCs. Electron microscopy revealed Kupffer cells filled with damaged and parasitized erythrocytes, and haemoglobin degradation pigment. We conclude that ingestion and metabolism of parasitized erythrocytes by liver macrophages during malaria infection decreases their organelle motion with likely consequences of compromised host defences.
PMCID: PMC3061090  PMID: 21068031
erythrophagocytosis; phagolysosomes; cell motility; magnetometry
4.  Magnetometric evaluation of toxicities of chemicals to the lungs and cells 
Because the lungs are exposed to airborne hazardous materials, alveolar macrophages (AMs) play a major role in defending against the exposure to various noxious chemical substances. In this study, we reviewed magnetometric investigations of the effects of various chemicals on the lungs and AMs. Magnetometry, using magnetite as an indicator, was used to evaluate the effects of certain chemicals on the lung and AMs. A rapid decrease of the remanent magnetic field after the cessation of external magnetization, a phenomenon called relaxation, was impaired when the lungs and macrophages were exposed to toxic substances. The delayed in vivo relaxation observed in the lungs exposed to magnetite and gallium arsenide was almost identical to the in vitro relaxation observed in the AMs exposed to the same materials. Delayed relaxation was observed in the AMs exposed to silica dust; various fibers, such as chrysotile and some man-made mineral fibers; and toxic arsenic and cadmium compounds. The extracellular release of lactate dehydrogenase activity was found in the AMs exposed to the chemicals. Relaxation is attributed to the cytoskeleton-driven rotation of phagosomes containing magnetite. While the exact mechanism of delayed relaxation due to exposure to harmful chemicals remains to be clarified, cell magnetometry appears to be useful for the safety screening of chemical substances.
PMCID: PMC2886888  PMID: 21432545
Magnetometry; Toxicity; Lung; Macrophage; Chemicals
5.  Ultrafine particles cause cytoskeletal dysfunctions in macrophages: role of intracellular calcium 
Particulate air pollution is reported to cause adverse health effects in susceptible individuals. Since most of these particles are derived form combustion processes, the primary composition product is carbon with a very small diameter (ultrafine, less than 100 nm in diameter). Besides the induction of reactive oxygen species and inflammation, ultrafine particles (UFP) can cause intracellular calcium transients and suppression of defense mechanisms of alveolar macrophages, such as impaired migration or phagocytosis.
In this study the role of intracellular calcium transients caused by UFP was studied on cytoskeleton related functions in J774A.1 macrophages. Different types of fine and ultrafine carbon black particles (CB and ufCB, respectively), such as elemental carbon (EC90), commercial carbon (Printex 90), diesel particulate matter (DEP) and urban dust (UD), were investigated. Phagosome transport mechanisms and mechanical cytoskeletal integrity were studied by cytomagnetometry and cell viability was studied by fluorescence microscopy. Macrophages were exposed in vitro with 100 and 320 μg UFP/ml/million cells for 4 hours in serum free medium. Calcium antagonists Verapamil, BAPTA-AM and W-7 were used to block calcium channels in the membrane, to chelate intracellular calcium or to inhibit the calmodulin signaling pathways, respectively.
Impaired phagosome transport and increased cytoskeletal stiffness occurred at EC90 and P90 concentrations of 100 μg/ml/million cells and above, but not with DEP or UD. Verapamil and W-7, but not BAPTA-AM inhibited the cytoskeletal dysfunctions caused by EC90 or P90. Additionally the presence of 5% serum or 1% bovine serum albumin (BSA) suppressed the cytoskeletal dysfunctions. Cell viability showed similar results, where co-culture of ufCB together with Verapamil, W-7, FCS or BSA produced less cell dead compared to the particles only.
PMCID: PMC1262770  PMID: 16202162
Ultrafine particles; cytoskeleton; stiffness; viscoelasticity; phagosome transport; relaxation; intracellular calcium
6.  Viscoelastic shear properties of the fresh porcine lens 
To determine the viscoelastic properties of the porcine lens
Linear viscoelastic shear properties of the stroma of four porcine lenses were measured within 5 hours post‐mortem, using sinusoidal oscillatory shear deformation. The elastic shear modulus, viscous shear modulus, dynamic viscosity, damping ratio, and phase shift of the lenses were quantified by a controlled‐strain, linear simple‐shear rheometer at frequencies of 10–50 Hz.
The mean viscoelastic properties and their standard deviations across the frequencies examined were: the elastic shear modulus, G′ = 6.2±4.0 Pa, the viscous shear modulus, G″ = 19.2±2.5 Pa, the dynamic viscosity, η′ = 0.16±0.1 Pa•sec, the damping ratio ζ = 4.06±1.25, and the phase shift, δ =  76°± 5.6°.
The measured viscoelastic shear properties of the porcine lens reflect a low dynamic viscosity with a high damping ratio. The porcine lens is viscoelastic and is more viscous than elastic. The magnitude of the complex shear modulus of the porcine lens, |G*|, is similar to the shear modulus of the young human lens. Understanding these viscoelastic properties of the natural lens may provide guidance in developing a lens substitute capable of accommodation in the post cataract patient.
PMCID: PMC1857677  PMID: 17035268
7.  Shear thickening of F-actin networks crosslinked with non-muscle myosin IIB 
Soft matter  2011;2011(7):3228-3233.
The material properties of cytoskeletal F-actin networks facilitate a broad range of cellular behaviors, whereby in some situations cell shape is preserved in the presence of force and, at other times, force results in irreversible shape change. These behaviors strongly suggest that F-actin networks can variably deform elastically or viscously. While a significant amount is known about the regulation of the elastic stiffness of F-actin networks, our understanding of the regulation of viscous behaviors of F-actin networks is largely lacking. Here, we study the rheological behavior of F-actin networks formed with heavy meromyosin non-muscle IIB (NMMIIB). We show that NMMIIB quenched with ADP crosslinks F-actin into networks that, for sufficient densities, display stress stiffening behavior. By performing a series of creep tests, we show that densely crosslinked actin/NMMIIB–ADP networks undergo viscous deformation over a wide range of stresses, ranging from 0.001 to 10 Pa. At high stresses, networks that stress stiffen are also observed to shear thicken, whereby the effective viscosity increases as a function of stress. Shear thickening results in a reduction in the extent of irreversible, viscous deformation in actin/NMMIIB–ADP networks at high stresses compared to that expected for a linear viscoelastic material. Thus, viscous deformation contributes less to the overall mechanical response at high levels of applied force. Our results indicate mechanisms by which the fluid-like nature of the actomyosin cytoskeleton can be reduced under high load.
PMCID: PMC3088166  PMID: 21552431
8.  Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis. 
Journal of Clinical Investigation  1981;68(1):259-269.
Neutrophils are a characteristic feature of the alveolitis of idiopathic pulmonary fibrosis (IPF). a chronic disorder limited to lung. One mechanism by which neutrophils may be selectively attracted to lung and not other tissues is via the secretion of the neutrophil-specific chemotactic factor by alveolar macrophages. To evaluate the role of alveolar macrophages in modulating the migration of neutrophils to he lung in IPF, alveolar macrophages, obtained by bronchoalveolar lavage of patients with IPF, were evaluated for their ability to release a chemotactic factor for neutrophils. Unstimulated alveolar macrophages from normal individuals did not release the factor. In patients with IPF, there was a significant correlation between the proportions of neutrophils in lavage fluid and the release of a chemotactic factor for neutrophils by alveolar macrophages (p less than 0.001). The chemotactic factor released by IPF alveolar macrophages was of low molecular weight (400-600), at least partially lipid in nature, and preferentially attracted neutrophils compared with monocytes. Several lines of evidence suggested that immune complexes in the lung stimulated alveolar macrophages of patients with IPF to release the chemotactic factor. First, immune complexes stimulated normal macrophages to release the factor.Second, there was a significant correlation between the release of the chemotactic factor by IPF alveolar macrophages and the levels of immune complexes in bronchoalveolar lavage fluid. Third, bronchoalveolar lavage fluid containing immune complexes stimulated normal macrophages to release the factor. Fourth, IPF alveolar macrophages that released large amounts of the chemotactic factor had an apparent suppression of their immunoglobulin (Ig)G Fc receptor function, suggesting that immune complexes were bound to their surface. In contrast, the IgG Fc receptor function of IPF alveolar macrophages that released only small amounts of the factor was similar to that of normal macrophages. These studies suggest that neutrophils are attracted to the lung in patients with IPF by a potent chemotactic factor released by alveolar macrophages that have been stimulated, in vivo, via their IgG Fc receptor by immune complexes.
PMCID: PMC370793  PMID: 7251862
9.  Cylinders vs. Spheres: Biofluid Shear Thinning in Driven Nanoparticle Transport 
Annals of biomedical engineering  2010;38(11):10.1007/s10439-010-0084-5.
Increasingly, the research community applies magnetophoresis to micro and nanoscale particles for drug delivery applications and the nanoscale rheological characterization of complex biological materials. Of particular interest is the design and transport of these magnetic particles through entangled polymeric fluids commonly found in biological systems. We report the magnetophoretic transport of spherical and rod-shaped particles through viscoelastic, entangled solutions using lambda-phage DNA (λ-DNA) as a model system. In order to understand and predict the observed phenomena, we fully characterize three fundamental components: the magnetic field and field gradient, the shape and magnetic properties of the probe particles, and the macroscopic rheology of the solution. Particle velocities obtained in Newtonian solutions correspond to macroscale rheology, with forces calculated via Stokes Law. In λ-DNA solutions, nanorod velocities are 100 times larger than predicted by measured zero-shear viscosity. These results are consistent with particles experiencing transport through a shear thinning fluid, indicating magnetically driven transport in shear thinning may be especially effective and favor narrow diameter, high aspect ratio particles. A complete framework for designing single-particle magnetic-based delivery systems results when we combine a quantified magnetic system with qualified particles embedded in a characterized viscoelastic medium.
PMCID: PMC3858002  PMID: 20571853
Shape effects; Drug delivery; Nanorods; Nanowires; Microrheology; DNA; Magnetic bead rheology
10.  Computational Analysis of Viscoelastic Properties of Crosslinked Actin Networks 
PLoS Computational Biology  2009;5(7):e1000439.
Mechanical force plays an important role in the physiology of eukaryotic cells whose dominant structural constituent is the actin cytoskeleton composed mainly of actin and actin crosslinking proteins (ACPs). Thus, knowledge of rheological properties of actin networks is crucial for understanding the mechanics and processes of cells. We used Brownian dynamics simulations to study the viscoelasticity of crosslinked actin networks. Two methods were employed, bulk rheology and segment-tracking rheology, where the former measures the stress in response to an applied shear strain, and the latter analyzes thermal fluctuations of individual actin segments of the network. It was demonstrated that the storage shear modulus (G′) increases more by the addition of ACPs that form orthogonal crosslinks than by those that form parallel bundles. In networks with orthogonal crosslinks, as crosslink density increases, the power law exponent of G′ as a function of the oscillation frequency decreases from 0.75, which reflects the transverse thermal motion of actin filaments, to near zero at low frequency. Under increasing prestrain, the network becomes more elastic, and three regimes of behavior are observed, each dominated by different mechanisms: bending of actin filaments, bending of ACPs, and at the highest prestrain tested (55%), stretching of actin filaments and ACPs. In the last case, only a small portion of actin filaments connected via highly stressed ACPs support the strain. We thus introduce the concept of a ‘supportive framework,’ as a subset of the full network, which is responsible for high elasticity. Notably, entropic effects due to thermal fluctuations appear to be important only at relatively low prestrains and when the average crosslinking distance is comparable to or greater than the persistence length of the filament. Taken together, our results suggest that viscoelasticity of the actin network is attributable to different mechanisms depending on the amount of prestrain.
Author Summary
The actin cytoskeleton provides structural integrity to a cell, is highly dynamic, and plays a central role in a wide variety of phenomena such as migration and the sensation of external forces. For years, researchers have studied the mechanics of the cytoskeleton by creating actin gels in the laboratory in combination with proteins that bridge between and reinforce the actin gel found inside cells. These gels, however, failed to replicate many aspects of cell behavior. Recent studies have shown that tension within the cytoskeleton contributes to the observed stiffness of cells. Still, our understanding of cytoskeletal mechanics is incomplete, and many observed phenomena cannot be explained by existing models. Here, we simulate a three-dimensional network containing actin filaments linked together by other proteins. We studied the relative contributions of thermal fluctuations of the network and the stiffness of filaments and linking proteins. Under conditions that replicate those in a cell, properties of the linking proteins are surprisingly significant, as is the stiffness of the actin filament to stretching. Thermal fluctuations are relatively unimportant, but become more so at low levels of resting tension. At high tensions, a small fraction of filaments support a majority of the load.
PMCID: PMC2703781  PMID: 19609348
11.  Mechanisms, measurement, and significance of lung macrophage function. 
Macrophages exist throughout the body. They have critical roles in the peritoneal cavity, bone marrow, skin, spleen, liver, and elsewhere. Their migratory patterns, phagocytic behavior, immunologic roles, and secretory potential are pivotal to both defense mechanisms and to the pathogenesis of disease. Macrophages have been implicated recently in such diverse disease processes as arthritis, AIDS, and juvenile onset diabetes. It is important to recognize the existence of other lung macrophages besides alveolar macrophages. Macrophages exist in small and large airways above and below the mucus. They may release chemotactic factors and a variety of mediators. They ingest and degrade antigens and are microbicidal. Interstitial macrophages are in direct contact with the extracellular matrix as well as other cells in pulmonary connective tissue such as fibroblasts. Thus, release of mediators or enzymes by interstitial macrophages can have a profound effect. Pulmonary intravascular macrophages are resident cells within the pulmonary capillaries of some species. They avidly remove particles and pathogens from circulating blood and secrete inflammatory mediators. Finally, pleural macrophages are involved in the fate and consequences of inhaled particles, especially fibers. A key attribute of macrophages is motility. Movement is an essential step in phagocytosis. There can be no particle binding or ingestion unless macrophage-particle contact occurs. To what extent and by what mechanisms do alveolar macrophages move on the alveolar epithelium? We have used optical methods as well as magnetometry to describe macrophage motility. Lung macrophages express an array of contractile proteins that are responsible for spreading, migration, phagocytosis, and the controlled intracellular motions of phagosomes and lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1519548  PMID: 1396468
12.  MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis 
PLoS Medicine  2008;5(4):e93.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.
Methods and Findings
We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins—MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A—that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%–100%) and specificity of 98.1% (95% CI 89.9%–100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%–100%) and specificity of 87.2% (95% CI 72.6%–95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%).
Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.
Naftali Kaminski and colleagues find increased levels of specific proteins in the bloodstream of individuals with idiopathic pulmonary fibrosis, and suggest that these proteins may ultimately provide a biomarker for the disease.
Editors' Summary
Idiopathic pulmonary fibrosis (IPF) is a serious disease in which the lungs become progressively scarred or thickened for unknown reasons. In healthy people, air is taken in through the mouth or nose and travels down the windpipe into tubes in the lungs called the airways. Each airway has many small branches that end in alveoli, tiny air sacs with thin walls that are surrounded by small blood vessels called capillaries. When air reaches the alveoli, the oxygen in it passes into the bloodstream and is taken to the organs of the body to keep them working. In IPF, the alveoli and the space around them (the “interstitial” area) gradually become scarred and thickened, which stops oxygen's movement into the bloodstream. When only small areas of the lung are scarred, IPF may cause no symptoms. But, as more of the lung becomes damaged, IPF eventually causes breathlessness, even when resting. There is no effective treatment for IPF, although steroids and drugs that suppress the body's immune system are often tried in an attempt to slow its progression. On average, half of the people with IPF die within three years of diagnosis, often from respiratory or heart failure.
Why Was This Study Done?
It can be difficult to diagnose IPF—there are many lung diseases with similar symptoms, including numerous other interstitial lung diseases—and currently, physicians can only follow the progression of IPF by repeatedly testing their patients' lung function or by doing multiple chest X-rays. If proteins could be identified whose level in blood indicated disease activity (so-called “peripheral blood biomarkers”), it would be easier to diagnose and monitor patients. In addition, the identification of such biomarkers might suggest new drug targets for the treatment of IPF. In this study, the researchers look for peripheral blood biomarkers in IPF by using a “multiplex analysis” system to measure the level of several proteins in patient blood samples simultaneously.
What Did the Researchers Do and Find?
The researchers measured the levels of 49 plasma proteins (plasma is the fluid part of blood) in 74 patients with IPF and 53 healthy people (controls) and used a technique called “recursive partitioning” to define a five-protein signature that distinguished patients from unaffected study participants (controls). Matrix metalloproteinase 7 (MMP7) and MMP1—the two plasma proteins whose levels were most increased in patients with IPF compared to controls—were key components of this signature. Concentrations of MMP7 and MMP1 were higher in bronchoalveolar lavage samples (fluid obtained by washing out the lungs with saline) and in lung tissue samples from patients with IPF than in similar samples taken from healthy individuals. Plasma concentrations of MMP7 and MMP1 were significantly higher in patients with IPF than in patients with hypersensitivity pneumonitis, an interstitial lung disease that mimics IPF, but not increased in patients with chronic obstructive pulmonary disease or sarcoidosis, two other lung diseases. In an independent validation group, patients with IPF and familial pulmonary fibrosis had increased plasma concentrations of MMP7 and MMP1 that correlated with the severity of their disease. In addition, MMP7 concentrations were raised in close relatives of people with familial pulmonary fibrosis who had normal lung function tests but some lung scarring.
What Do These Findings Mean?
These findings provide evidence for a protein signature in the blood for IPF and suggest MMP1 and MMP7 may be useful as biomarkers for IPF. These two matrix metalloproteinases have previously been suggested to be involved in the development of IPF. However, additional work is probably needed to confirm that increased plasma concentrations MMP7 and MMP1 are specific for IPF, since it may be that these markers will not distinguish IPF from other interstitial lung diseases.
Additional Information.
Please access these Web sites via the online version of this summary at
Read a related PLoS Medicine Perspective article
The MedlinePlus Encyclopedia has a page on idiopathic pulmonary fibrosis (in English and Spanish) and on pulmonary fibrosis
The US National Heart Lung and Blood Institute and the British Lung Foundation also provide information on IPF for patients and relatives
Some of the researchers involved in this study provide more details about what might go wrong in IPF in a recent PLoS Medicine article
PMCID: PMC2346504  PMID: 18447576
13.  Twist: A Regulator of Epithelial-Mesenchymal Transition in Lung Fibrosis 
PLoS ONE  2009;4(10):e7559.
Several studies have implicated viral infection as an important factor in the pathogenesis of IPF and related fibrotic lung disorders. Viruses are thought to cause epithelial cell injury and promote epithelial-mesenchymal transition (EMT), a process whereby differentiated epithelial cells undergo transition to a mesenchymal phenotype, and considered a source of fibroblasts in the setting of lung injury. We have demonstrated an association between the epithelial injury caused by chronic herpes virus infection with the murine γ-herpes virus, MHV68, and lung fibrosis. We hypothesize that EMT in this model of virus-induced pulmonary fibrosis is driven by the expression of the transcription factor Twist.
In vitro MHV68 infection of murine lung epithelial cells induced expression of Twist, and mesenchymal markers. Stable overexpression of Twist promoted EMT in MLE15 lung epithelial cells. Transient knockdown expression of Twist resulted in preservation of epithelial phenotype after in vitro MHV68 infection. In concordance, high expression of Twist was found in lung epithelial cells of MHV68 infected mice, but not in mock infected mice. Alveolar epithelial cells from lung tissue of idiopathic pulmonary fibrosis (IPF) patients were strongly positive for Twist. These cells demonstrated features of EMT with low expression of E-cadherin and upregulation of the mesenchymal marker N-cadherin. Finally, IPF tissue with high Twist protein levels was also positive for the herpesvirus, EBV.
We conclude that Twist contributes to EMT in the model of virus-induced pulmonary fibrosis. We speculate that in some IPF cases, γ-herpes virus infection with EBV might be a source of injury precipitating EMT through the expression of Twist.
PMCID: PMC2761603  PMID: 19851501
14.  High-Resolution Mechanical Imaging of Glioblastoma by Multifrequency Magnetic Resonance Elastography 
PLoS ONE  2014;9(10):e110588.
To generate high-resolution maps of the viscoelastic properties of human brain parenchyma for presurgical quantitative assessment in glioblastoma (GB).
Twenty-two GB patients underwent routine presurgical work-up supplemented by additional multifrequency magnetic resonance elastography. Two three-dimensional viscoelastic parameter maps, magnitude |G*|, and phase angle φ of the complex shear modulus were reconstructed by inversion of full wave field data in 2-mm isotropic resolution at seven harmonic drive frequencies ranging from 30 to 60 Hz.
Mechanical brain maps confirmed that GB are composed of stiff and soft compartments, resulting in high intratumor heterogeneity. GB could be easily differentiated from healthy reference tissue by their reduced viscous behavior quantified by φ (0.37±0.08 vs. 0.58±0.07). |G*|, which in solids more relates to the material's stiffness, was significantly reduced in GB with a mean value of 1.32±0.26 kPa compared to 1.54±0.27 kPa in healthy tissue (P = 0.001). However, some GB (5 of 22) showed increased stiffness.
GB are generally less viscous and softer than healthy brain parenchyma. Unrelated to the morphology-based contrast of standard magnetic resonance imaging, elastography provides an entirely new neuroradiological marker and contrast related to the biomechanical properties of tumors.
PMCID: PMC4206430  PMID: 25338072
15.  Regulation of the effects of TGF-β1 by activation of latent TGF-β1 and differential expression of TGF-β receptors (TβR-I and TβR-II) in idiopathic pulmonary fibrosis 
Thorax  2001;56(12):907-915.
BACKGROUND—Idiopathic pulmonary fibrosis (IPF) is characterised by subpleural fibrosis that progresses to involve all areas of the lung. The expression of transforming growth factor-β1 (TGF-β1), a potent regulator of connective tissue synthesis, is increased in lung sections of patients with IPF. TGF-β1 is generally released in a biologically latent form (L-TGF-β1). Before being biologically active, TGF-β must be converted to its active form and interact with both TGF-β receptors type I and II (TβR-I and TβR-II). TGF-β latency binding protein 1 (LTBP-1), which facilitates the release and activation of L-TGF-β1, is also important in the biology of TGF-β1.
METHODS—Open lung biopsy samples from patients with IPF and normal controls were examined to localise TβR-I, TβR-II, and LTBP-1. Alveolar macrophages (AM) and bronchoalveolar lavage (BAL) fluid were examined using the CCL-64 bioassay to determine if TGF-β is present in its active form in the lungs of patients with IPF.
RESULTS—Immunoreactive L-TGF-β1 was present in all lung cells of patients with IPF except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced IPF. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with IPF secreted 1.6 (0.6) fmol and 4.1 (1.9) fmol active TGF-β, respectively, while AM from the lower lobes of control patients secreted no active TGF-β (p⩽0.01 for TGF-β in the conditioned media from AM obtained from the lower lobes of IPF patients v normal controls). The difference in percentage active TGF-β secreted by AM from the lower lobes of patients with IPF and the lower lobes of control patients was significant (p⩽0.01), but the difference between the total TGF-β secreted from these lobes was not significant. The difference in active TGF-β in conditioned media of AM from the upper and lower lobes of patients with IPF was also not statistically significant. BAL fluid from the upper and lower lobes of patients with IPF contained 0.7 (0.2) fmol and 2.9 (1.2) fmol active TGF-β, respectively (p⩽0.03). The percentage of active TGF-β in the upper and lower lobes was 17.6 (1.0)% and 78.4 (1.6)%, respectively (p⩽0.03). In contrast, BAL fluid from control patients contained small amounts of L-TGF-β. Using immunostaining, both TβR-I and TβR-II were present on all cells of normal lungs but TβR-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with IPF. TGF-β1 inhibits epithelial cell proliferation and a lack of TβR-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both TβRs on fibroblasts is likely to result in a response to TGF-β1 for synthesis of connective tissue proteins. Our findings show that biologically active TGF-β1 is only present in the lungs of patients with IPF. In addition, the effects of TGF-β1 on cells may be further regulated by the expression of TβRs.
CONCLUSION—Activation of L-TGF-β1 and the differential expression of TβRs may be important in the pathogenesis of remodelling and fibrosis in IPF.

PMCID: PMC1745982  PMID: 11713352
16.  Multiple Peptidoglycan Modification Networks Modulate Helicobacter pylori's Cell Shape, Motility, and Colonization Potential 
PLoS Pathogens  2012;8(3):e1002603.
Helical cell shape of the gastric pathogen Helicobacter pylori has been suggested to promote virulence through viscosity-dependent enhancement of swimming velocity. However, H. pylori csd1 mutants, which are curved but lack helical twist, show normal velocity in viscous polymer solutions and the reason for their deficiency in stomach colonization has remained unclear. Characterization of new rod shaped mutants identified Csd4, a DL-carboxypeptidase of peptidoglycan (PG) tripeptide monomers and Csd5, a putative scaffolding protein. Morphological and biochemical studies indicated Csd4 tripeptide cleavage and Csd1 crosslinking relaxation modify the PG sacculus through independent networks that coordinately generate helical shape. csd4 mutants show attenuation of stomach colonization, but no change in proinflammatory cytokine induction, despite four-fold higher levels of Nod1-agonist tripeptides in the PG sacculus. Motility analysis of similarly shaped mutants bearing distinct alterations in PG modifications revealed deficits associated with shape, but only in gel-like media and not viscous solutions. As gastric mucus displays viscoelastic gel-like properties, our results suggest enhanced penetration of the mucus barrier underlies the fitness advantage conferred by H. pylori's characteristic shape.
Author Summary
The only habitat of Helicobacter pylori is the human stomach, where it can promote stomach ulcers and cancer. Cells lining the stomach are protected from luminal acid by a thick layer of gastric mucus composed of polymerized gastric mucins. Gastric mucin undergoes a physical transition between a viscoelastic solution at neutral pH to a viscoelastic gel-like state at low pH. Helical rod shape in bacteria has been suggested to enhance swimming velocity in viscous solutions by a cork-screw mechanism, but H. pylori mutants lacking helical twist show normal swimming velocity in viscous polymer solutions used in prior studies comparing motility across bacterial species. These same mutants, however, show diminished colonization suggesting helical shape promotes stomach infection by another mechanism. Here we identified Csd4, a protease of cell wall tripeptides, which induces curvature in the cell body independently from the changes in cell wall crosslinking previously shown to promote helical twist. Cells lacking Csd4 form straight rods that also show colonization defects but normal velocity in several viscous polymer solutions. Upon examination of motility in gel-like media, however, we discovered that elimination or exaggeration of cell curvature perturbs motility. Thus H. pylori's helical shape may aid penetration of gel-like stomach mucus.
PMCID: PMC3310797  PMID: 22457625
17.  Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers 
This study explored the cellular and biological interrelationships involved in Idiopathic Pulmonary Fibrosis (IPF) lung tissue remodelling using immunohistochemical analysis.
Methods and results
IPF and control lung tissues were examined for localisation of Epithelial Mesenchymal Transition (EMT), proliferation and growth factor markers assessing their relationship to key histological aberrations. E-cadherin was expressed in IPF and control (Alveolar type II) ATII cells (>75%). In IPF, mean expression of N-cadherin was scanty (<10%): however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status (Pearson correlation score 0.557). Twist was expressed within fibroblastic foci but not in ATII cells. Transforming Growth Factor- β (TGF-β) protein expression was significantly increased in IPF ATII cells with variable expression within fibroblastic foci. Antigen Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. Collagen I and α-smooth muscle actin (α-SMA) were strongly expressed within fibroblastic foci (>75%); cytoplasmic collagen I in ATII cells was present in 3 IPF cases. IPF ATII cells demonstrated variable Surfactant Protein-C (SP-C).
The pathogenesis of IPF is complex and involves multiple factors, possibly including EMT. Histological analysis suggests TGF-β-stimulated myofib rob lasts initiate a contractile response within established fibroblastic foci while proliferating ATII cells attempt to instigate alveolar epithelium repair. Marker expression (N-cadherin and Ki-67) correlation with histological disease activity (as reflected by fibroblastic foci extent) may emerge as future prognostic indicators for IPF.
PMCID: PMC3267487  PMID: 22295148
Idiopathic Pulmonary Fibrosis; immunohistochemistry; epithelial-mesenchymal transition; tissue repair and remodelling; prognostic markers
18.  Resolving the Role of Actoymyosin Contractility in Cell Microrheology 
PLoS ONE  2009;4(9):e7054.
Einstein's original description of Brownian motion established a direct relationship between thermally-excited random forces and the transport properties of a submicron particle in a viscous liquid. Recent work based on reconstituted actin filament networks suggests that nonthermal forces driven by the motor protein myosin II can induce large non-equilibrium fluctuations that dominate the motion of particles in cytoskeletal networks. Here, using high-resolution particle tracking, we find that thermal forces, not myosin-induced fluctuating forces, drive the motion of submicron particles embedded in the cytoskeleton of living cells. These results resolve the roles of myosin II and contractile actomyosin structures in the motion of nanoparticles lodged in the cytoplasm, reveal the biphasic mechanical architecture of adherent cells—stiff contractile stress fibers interdigitating in a network at the cell cortex and a soft actin meshwork in the body of the cell, validate the method of particle tracking-microrheology, and reconcile seemingly disparate atomic force microscopy (AFM) and particle-tracking microrheology measurements of living cells.
PMCID: PMC2737638  PMID: 19756147
19.  Acute exacerbations in patients with idiopathic pulmonary fibrosis 
Respiratory Research  2013;14(1):86.
Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial lung disease that primarily affects older adults. Median survival after diagnosis is 2–3 years. The clinical course of IPF may include periods of acute deterioration in respiratory function, which are termed acute exacerbations of IPF (AEx-IPF) when a cause cannot be identified. AEx-IPF may represent a sudden acceleration of the underlying disease process of IPF, or a biologically distinct pathological process that is clinically undiagnosed. An AEx-IPF can occur at any time during the course of IPF and may be the presenting manifestation. The incidence of AEx-IPF is hard to establish due to variation in the methodology used to assess AEx-IPF in different studies, but AEx-IPF are believed to occur in between 5 and 10% of patients with IPF every year. Risk factors for AEx-IPF are unclear, but there is evidence that poorer lung function increases the risk of an AEx-IPF and reduces the chances of a patient surviving an AEx-IPF. The presence of comorbidities such as gastroesophageal reflux disease (GERD) and pulmonary hypertension may also increase the risk of an AEx-IPF. AEx-IPF are associated with high morbidity and mortality. Patients who experience an AEx-IPF show a worsened prognosis and AEx-IPF are believed to reflect disease progression in IPF. Current treatments for AEx-IPF have only limited data to support their effectiveness. The latest international treatment guidelines state that supportive care remains the mainstay of treatment for AEx-IPF, but also give a weak recommendation for the treatment of the majority of patients with AEx-IPF with corticosteroids. There is emerging evidence from clinical trials of investigational therapies that chronic treatment of IPF may reduce the incidence of AEx-IPF. Additional clinical trials investigating this are underway.
PMCID: PMC3765544  PMID: 23964926
Acute exacerbation; Idiopathic pulmonary fibrosis (IPF); Impact; Management; Prevention; Treatment
20.  The Phagocytosis and Toxicity of Amorphous Silica 
PLoS ONE  2011;6(2):e14647.
Inhalation of crystalline silica is known to cause an inflammatory reaction and chronic exposure leads to lung fibrosis and can progress into the disease, silicosis. Cultured macrophages bind crystalline silica particles, phagocytose them, and rapidly undergo apoptotic and necrotic death. The mechanism by which particles are bound and internalized and the reason particles are toxic is unclear. Amorphous silica has been considered to be a less toxic form, but this view is controversial. We compared the uptake and toxicity of amorphous silica to crystalline silica.
Methodology/Principal Findings
Amorphous silica particles are phagocytosed by macrophage cells and a single internalized particle is capable of killing a cell. Fluorescent dextran is released from endo-lysosomes within two hours after silica treatment and Caspase-3 activation occurs within 4 hours. Interestingly, toxicity is specific to macrophage cell lines. Other cell types are resistant to silica particle toxicity even though they internalize the particles.
The large and uniform size of the spherical, amorphous silica particles allowed us to monitor them during the uptake process. In mCherry-actin transfected macrophages, actin rings began to form 1-3 minutes after silica binding and the actin coat disassembled rapidly following particle internalization. Pre-loading cells with fluorescent dextran allowed us to visualize the fusion of phagosomes with endosomes during internalization. These markers provided two new ways to visualize and quantify particle internalization. At 37°C the rate of amorphous silica internalization was very rapid regardless of particle coating. However, at room temperature, opsonized silica is internalized much faster than non-opsonized silica.
Our results indicate that amorphous and crystalline silica are both phagocytosed and both toxic to mouse alveolar macrophage (MH-S) cells. The pathway leading to apoptosis appears to be similar in both cases. However, the result suggests a mechanistic difference between FcγRIIA receptor-mediated and non-opsonized silica particle phagocytosis.
PMCID: PMC3032735  PMID: 21311600
21.  Mononuclear Phagocytes and Airway Epithelial Cells: Novel Sources of Matrix Metalloproteinase-8 (MMP-8) in Patients with Idiopathic Pulmonary Fibrosis 
PLoS ONE  2014;9(5):e97485.
Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps.
We measured MMP-8 levels and forms in blood and lung samples from IPF patients versus controls using ELISAs, western blotting, and qPCR, and assessed whether MMP-8 plasma levels in 73 IPF patients correlate with rate of lung function decline and mortality. We used immunostaining to localize MMP-8 expression in IPF lungs. We quantified MMP-8 levels and forms in blood leukocytes from IPF patients versus controls.
IPF patients have increased BALF, whole lung, and plasma levels of soluble MMP-8 protein. Active MMP-8 is the main form elevated in IPF lungs. MMP-8 mRNA levels are increased in monocytes from IPF patients, but IPF patients and controls have similar levels of MMP-8 in PMNs. Surprisingly, macrophages and airway epithelial cells are the main cells expressing MMP-8 in IPF lungs. Plasma and BALF MMP-8 levels do not correlate with decline in lung function and/or mortality in IPF patients.
Blood and lung MMP-8 levels are increased in IPF patients. Active MMP-8 is the main form elevated in IPF lungs. Surprisingly, blood monocytes, lung macrophages, and airway epithelial cells are the main cells in which MMP-8 is upregulated in IPF patients. Plasma and BALF MMP-8 levels are unlikely to serve as a prognostic biomarker for IPF patients. These results provide new information about the expression patterns of MMP-8 in IPF patients.
PMCID: PMC4020836  PMID: 24828408
22.  Idiopathic pulmonary fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.
PMCID: PMC2330030  PMID: 18366757
23.  The Effect of Enterohemorrhagic E. coli Infection on the Cell Mechanics of Host Cells 
PLoS ONE  2014;9(11):e112137.
Enterohaemorrhagic E. coli (EHEC) is a type of human pathogenic bacteria. The main virulence characteristics of EHEC include the formation of attaching and effacing lesions (A/E lesions) and the production of one or more Shiga-like toxins, which may induce human uremic complications. When EHEC infects host cells, it releases translocated intimin receptor (Tir) and effector proteins inside the host cells, inducing the rearrangement and accumulation of the F-actin cytoskeleton, a phenotype leading to the formation of pedestals in the apical cell surface, and the growth of stress fibers at the base of the cells. To examine the effect of EHEC infection on cell mechanics, we carried out a series of experiments to examine HeLa cells with and without EHEC infection to quantify the changes in (1) focal adhesion area, visualized by anti-vinculin staining; (2) the distribution and orientation of stress fibers; and (3) the intracellular viscoelasticity, via directional video particle tracking microrheology. Our results indicated that in EHEC-infected HeLa cells, the focal adhesion area increased and the actin stress fibers became thicker and more aligned. The cytoskeletal reorganization induced by EHEC infection mediated a dramatic increase in the cytoplasmic elastic shear modulus of the infected cells, and a transition in the viscoelastic behavior of the cells from viscous-like to elastic-like. These changes in mechanobiological characteristics might modulate the attachments between EHEC and the host cell to withstand exfoliation, and between the host cell and the extracellular matrix, and might also alter epithelial integrity.
PMCID: PMC4219835  PMID: 25369259
24.  Lung dust content in idiopathic pulmonary fibrosis: a study with scanning electron microscopy and energy dispersive x ray analysis. 
Examination with an optical microscope and polarised light is not sensitive enough to detect low diameter asbestos fibres. This limitation implies that some cases of asbestosis can be erroneously diagnosed as idiopathic pulmonary fibrosis (IPF) if asbestos bodies are not found in the standard examination of abnormal tissue. To determine whether IPF is over-diagnosed, a study was carried out with scanning electron microscopy (SEM) and energy dispersive x ray analysis (EDXA) on 25 samples previously diagnosed as IPF at the standard examination. Scanning electron microscopy will show the presence of low diameter fibres in the lung without tissue destruction, and these fibres can be identified using EDXA. The quantitative and qualitative results for lung tissue from patients diagnosed as having IPF were compared with the results of the examination of 25 samples of normal lung. Most of the samples from patients diagnosed as having IPF showed only occasional inorganic particles (less than 10 particles/SEM field at 160 x), results equivalent to the results obtained in normal lung. Two cases of IPF, however, showed innumerable asbestos fibres (greater than 100 fibres/SEM field). One of these two patients had an antecedent of brief exposure to asbestos. No environmental antecedent was found in the second patient. Asbestosis was the final diagnosis for these two patients. The examination of inorganic particles in normal lungs showed mainly non-fibrous silicates (61.4%) and particles of heavy elements (34.9%). Only one asbestos fibre was found (0.9%). It is concluded that standard pathological techniques overdiagnose IPF in a few cases in which asbestos bodies are not found with the optical microscope.
PMCID: PMC1012042  PMID: 2039745
25.  Detection of Alveolar Fibrocytes in Idiopathic Pulmonary Fibrosis and Systemic Sclerosis 
PLoS ONE  2013;8(1):e53736.
Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL.
We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts.
Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% [0.4–19.7] and 3.0% [2.7–3.7] of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts.
Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid.
PMCID: PMC3547062  PMID: 23341987

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