Topographic distribution of idiopathic pulmonary fibrosis: a hybrid physics- and agent-based model.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by excessive deposition of collagen and associated stiffening of lung tissue. While it is known that inflammation and dysfunction of fibroblasts are involved in disease development, it remains poorly understood how cells and their microenvironment interact to produce a characteristic subpleural pattern of high and low tissue density variations, called honeycombing, on CT images of patients with IPF. Since the pleura is stiffer than the parenchyma, we hypothesized that local stiffness of the underlying extracellular matrix can influence fibroblast activation and consequently the deposition of collagen, which in turn influences tissue stiffness in a positive feedback loop. APPROACH: We tested this hypothesis by developing a hybrid physics-based/agent-based computational model in which aberrant fibroblast activation is induced when cells migrate on stiff tissue. This activation then feeds back on itself via the altered mechanical environment that it creates by depositing collagen. MAIN RESULTS: The model produces power law distributions of both low- and high-attenuation area clusters and predicts the development of honeycombing only when mechanical rupture is allowed to take place in highly strained normal tissue surrounded by stiff fibrotic tissue. These predictions compare well with histologic data computed from CT images of patients with IPF. SIGNIFICANCE: We conclude that the clinical manifestation of subpleural honeycombing in IPF may result from fibroblasts entering into a positive feedback loop induced by the abnormally high tissue stiffness near the pleura.

A bronchoscopic oddity: nodular tracheobronchial amyloidosis.

Tracheobronchial amyloidosis is a rare disorder of unknown cause associated with the extracellular deposition of amyloid protein in a characteristic spatial structure of ß-sheet fibrils assembled into bundles. We present a case that represents the nodular form of tracheobronchial amyloidosis, which is the least common form of pulmonary amyloidosis with less than 20 cases reported so far. Patients with tracheobronchial amyloidosis may present with symptoms of dyspnea, localized wheezing, cough, hemoptysis, or recurrent pneumonias. The mainstay of the therapy is debridement of the symptomatic luminal obstruction with neodymium-doped yttrium aluminium garnet laser therapy. Other treatment strategies include airway stenting, external beam radiation therapy, bypass tracheostomy, or open surgical resection.

Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation.

RATIONALE: Transforming growth factor (TGF)-beta has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin alpha(v)beta6, a key activator of TGF-beta in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-beta at sites of alpha(v)beta6 up-regulation without affecting other homeostatic roles of TGF-beta. OBJECTIVES: To analyze the expression of alpha(v)beta6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of alpha(v)beta6-mediated TGF-beta activation in murine bleomycin-induced pulmonary fibrosis. METHODS: Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for alpha(v)beta6 expression. A range of concentrations of a monoclonal antibody that blocks alpha(v)beta6-mediated TGF-beta activation was evaluated in murine bleomycin-induced lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Alpha(v)beta6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, alpha(v)beta6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-beta inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers. CONCLUSIONS: Partial inhibition of TGF-beta using alpha(v)beta6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of alpha(v)beta6, an activator of the fibrogenic cytokine, TGF-beta, in human pulmonary fibrosis suggests that alpha(v)beta6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.

Linking parenchymal disease progression to changes in lung mechanical function by percolation.

RATIONALE: The mechanical dysfunction accompanying parenchymal diseases such as pulmonary fibrosis and emphysema may follow a different course from the progression of the underlying microscopic pathophysiology itself, particularly in the early stages. It is tempting to speculate that this may reflect the geographical nature of lung pathology. However, merely ascribing mechanical dysfunction of the parenchyma to the vagaries of lesional organization is unhelpful without some understanding of how the two are linked. OBJECTIVES: We attempt to forge such a link through a concept known as percolation, which has been invoked to account for numerous natural processes involving transmission of events across complex networks. METHODS: We numerically determined the bulk stiffness (corresponding to the inverse of lung compliance) of a network of springs representing the lung parenchyma. We simulated the development of fibrosis by randomly stiffening individual springs in the network, and the development of emphysema by preferentially cutting springs under the greatest tension. MEASUREMENTS AND MAIN RESULTS: When the number of stiff springs was increased to the point that they suddenly became connected across the network, the model developed a sharp increase in its bulk modulus. Conversely, when the cut springs became sufficiently numerous, the elasticity of the network fell to zero. These two conditions represent percolation thresholds that we show are mirrored structurally in both tissue pathology and macroscopic computed tomography images of human idiopathic fibrosis and emphysema. CONCLUSIONS: The concept of percolation may explain why the development of symptoms related to lung function and the development of parenchymal pathology often do not progress together.

Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice.

The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)-delta knockout (PKCdelta-/-) mice to demonstrate multiple roles of PKC-delta in the development of cell proliferation and inflammation after inhalation of chrysotile asbestos. At 3 days, asbestos-induced peribronchiolar cell proliferation in wild-type mice was attenuated in PKCdelta-/- mice. Cytokine profiles in bronchoalveolar lavage fluids showed increases in interleukin (IL)-1beta, IL-4, IL-6, and IL-13 that were decreased in PKCdelta-/- mice. At 9 days, microarray and quantitative reverse transcriptase-polymerase chain reaction analysis of lung tissues revealed increased mRNA levels of the profibrotic cytokine, IL-4, in asbestos-exposed wild-type mice but not PKCdelta-/- mice. PKCdelta-/- mice also exhibited decreased lung infiltration of polymorphonuclear cells, natural killer cells, and macrophages in bronchoalveolar lavage fluid and lung, as well as increased numbers of B lymphocytes and plasma cells. These changes were accompanied by elevated mRNA levels of immunoglobulin chains. These data show that modulation of PKC-delta has multiple effects on peribronchiolar cell proliferation, proinflammatory and profibrotic cytokine expression, and immune cell profiles in lung. These results also implicate targeted interruption of PKC-delta as a potential therapeutic option in asbestos-induced lung diseases.

Interleukin-12 is not essential for silicosis in mice.

BACKGROUND: Silicosis features foci of inflammation where macrophages and lymphocytes precede and accompany fibroblast proliferation, alveolar epithelial hyperplasia, and increased deposition of connective tissue matrix material. In the mouse following silica inhalation there is recruitment of natural killer-, B-, and CD4+ and CD8+ lymphocytes to the alveolar spaces, enlargement of bronchial-associated lymphoid tissues (BALT), and aggregation of lymphocytes surrounding small airways and blood vessels. A substantial fraction of the recruited lung lymphocytes produce interferon-gamma (IFN-gamma), and IFN-gamma gene-deleted mice develop less silicosis than wild-type mice. Interleukin-12 (IL-12) is an important pathway for driving the adaptive immune response towards a TH1-like phenotype. We hypothesized that IL-12 might stimulate lymphocyte activation and the up-regulation of IFN-gamma, and consequently be an essential mediator for silicosis. RESULTS: C57Bl/6 wild-type (WT) and IL-12 deficient (IL-12 KO) mice were exposed to sham-air or crystobalite silica (61 mg/m3) by inhalation for 5 hours/day for 12 days and then studied from 1 to 112 days after exposure. Mice exposed to sham-air had normal lung histology at all time points. WT mice exposed to titanium dioxide (72 mg/m3) showed pulmonary macrophage recruitment but no increase in lung collagen. Both WT and IL-12 KO mice exposed to silica showed similar progressive lung pathology, increased wet lung weight and increased total lung collagen (hydroxyproline). IL-12 p35 mRNA was not increased in either strain after silica exposure; IL-12 p40 mRNA was up-regulated after silica in WT mice and constitutively absent in the IL-12 KO mice. IL-18 mRNA was not increased after silica exposure. The expression of IL-15 (an important driver for innate immunity, Natural Killer cell activation, and IFN-gamma production) was abundant in air-exposed mice and was increased slightly in the lungs of mice with silicosis. CONCLUSION: The axis of IL-12 driving IFN-gamma production is not essential for the full manifestations of silicosis in mice exposed to a crystobalite silica aerosol.

Review: occupational and environmental lung disease.

Occupational and environmental lung disease is a vast topic. Therefore, this review focuses on areas that represent new clinical insights that have not been addressed recently in Current Opinion in Pulmonary Medicine. The topics are considered important for the future and emphasize diseases that strike large numbers of people or exposures that affect large segments of the population. This review highlights literature published between the years 2000 to 2001 related to air pollution, occupational asthma, lung diseases in agricultural workers, nylon flock workers lung disease, pneumoconiosis, and environmental exposure to biomass smoke, including environmental tobacco smoke. These publications highlight the changing world of occupational and environmental lung diseases. Traditionally, this field dealt with chronic diseases caused by very high levels of exposure to materials that affected virtually all workers to a similar degree. Disease could be recognized readily by characteristic symptoms, signs, and radiographic abnormalities. Dose-effect relationships were usually clear, and the solution to disease was generally to limit exposure for all workers. This approach served well for conditions such as coal workers pneumoconiosis or toxic responses to chlorine gas. The new world of occupational and environmental lung diseases often involves low levels of exposure to complex mixtures of materials that produce nonspecific or intermittent symptoms in a subgroup of exposed individuals. Interactions between genetic susceptibility, concomitant tobacco smoke exposure, and co-morbid diseases hugely complicate both diagnosis and prevention. New tools, and possibly new thought paradigms, are needed to detect, treat, and prevent occupational and environmental lung diseases in a changing world.