A 52-Year-Old Man Presented With Cough, Chest Pain, and a Mass in the Right Lung.

CASE PRESENTATION: A 52-year-old man, current smoker with a 50 pack-year history, presented to our department with cough, yellow sputum, and localized right chest pain. Chest radiograph revealed a large mass in the right upper lobe. He denied the presence of fever, night sweats, or weight loss. He has a medical history of COPD and anxiety disorder. He was receiving long-acting beta agonists/long-acting muscarinic antagonists as a treatment for COPD and quetiapine 100 mg for anxiety disorder.

A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination.

Mycobacterium tuberculosis (Mtb), the causative infectious agent of tuberculosis (TB), kills more individuals per year than any other infectious agent. Granulomas, the hallmark of Mtb infection, are complex structures that form in lungs, composed of immune cells surrounding bacteria, infected cells, and a caseous necrotic core. While granulomas serve to physically contain and immunologically restrain bacteria growth, some granulomas are unable to control Mtb growth, leading to bacteria and infected cells leaving the granuloma and disseminating, either resulting in additional granuloma formation (local or non-local) or spread to airways or lymph nodes. Dissemination is associated with development of active TB. It is challenging to experimentally address specific mechanisms driving dissemination from TB lung granulomas. Herein, we develop a novel hybrid multi-scale computational model, MultiGran, that tracks Mtb infection within multiple granulomas in an entire lung. MultiGran follows cells, cytokines, and bacterial populations within each lung granuloma throughout the course of infection and is calibrated to multiple non-human primate (NHP) cellular, granuloma, and whole-lung datasets. We show that MultiGran can recapitulate patterns of in vivo local and non-local dissemination, predict likelihood of dissemination, and predict a crucial role for multifunctional CD8+ T cells and macrophage dynamics for preventing dissemination.

Transplant Pulmonary Interventions: Translating Lung Transplant Interventions to Nontransplant Patients.

Roughly 10% of lung transplant recipients experience airway complications. Although the incidence has decreased dramatically since the first lung transplants were performed in the 1960s, airway complications have continued to adversely affect outcomes. Bronchoscopic interventions such as balloon dilation, airway stenting, and endobronchial electrocautery play an important role in ameliorating the morbidity and mortality associated with these complications. This review describes the array of bronchoscopic interventions used to treat airway complications after lung transplant and how these techniques can be used in nontransplant settings as well.

Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection.

Tuberculosis (TB) is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas) during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG) vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies) in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals.

A population model capturing dynamics of tuberculosis granulomas predicts host infection outcomes.

Granulomas play a centric role in tuberculosis (TB) infection progression. Multiple granulomas usually develop within a single host. These granulomas are not synchronized in size or bacteria load, and will follow different trajectories over time. How the fate of individual granulomas influence overall infection outcome at host scale is not understood, although computational models have been developed to predict single granuloma behavior. Here we present a within-host population model that tracks granulomas in two key organs during Mycobacteria tuberculosis (Mtb) infection: lung and lymph nodes (LN). We capture various time courses of TB progression, including latency and reactivation. The model predicts that there is no steady state; rather it is a continuous process of progressing to active disease over differing time periods. This is consistent with recently posed ideas suggesting that latent TB exists as a spectrum of states and not a single state. The model also predicts a dual role for granuloma development in LNs during Mtb infection: in early phases of infection granulomas suppress infection by providing additional antigens to the site of immune priming; however, this induces a more rapid reactivation at later stages by disrupting immune responses. We identify mechanisms that strongly correlate with better host-level outcomes, including elimination of uncontained lung granulomas by inducing low levels of lung tissue damage and inhibition of bacteria dissemination within the lung.

Incidence and aetiologies of pulmonary granulomatous inflammation: a decade of experience.

BACKGROUND AND OBJECTIVE: Granulomatous lung disease (GLD) is caused by a wide range of conditions. Often there is a need to correlate pathological findings with clinical, microbiological or radiological data to determine an aetiology. The aim of this study was to determine the different aetiologies of GLD over the past decade. METHODS: Among 2228 consecutive lung specimens from 1999 to 2011, 226 cases (10.1%) were positive for GLD. One hundred ninety patients were retrospectively reviewed and diagnoses were assigned based on availability of histological/clinical/microbiological correlation. RESULTS: A confident, probable and uncertain diagnosis was made in 68.4%, 13.2% and 18.4% patients. The aetiologies comprised infectious, non-infectious and uncertain in 54.7%, 26.8% and 18.4% patients. Mycobacterial infections constituted 27% of all patients, and included atypical, tuberculous and unclassified mycobacteria in order of frequency. Acid-fast bacilli (AFB) were visualized in tissue sections in 29% cases and cultured in 73% cases. Fungal infections comprised 27% of all cases, which included Coccidioides, Cryptococcus, Aspergillus and Histoplasma in order of frequency. Fungi were visualized in tissue sections with Gomori methenamine silver (GMS) stain in 83% patients and cultured in 52% cases. Sarcoidosis was the major non-infectious aetiology, constituting 21% of all patients. Necrosis in granulomas was associated with the presence of infection (P < 0.001). CONCLUSIONS: The aetiology in necrotizing GLD with negative AFB and GMS stains is most likely infectious due to atypical mycobacteria. Coccidioidomycosis was the most common fungal infection. The aetiology in non-necrotizing GLD is most likely non-infectious, probably sarcoidosis.

Pulmonary functional and morphological damage after exposure to tripoli dust.

Tripoli is a microcrystalline siliceous rock used to polish metals and precious stones. Its inhalation has been associated with increased prevalence of breathing complaints and pneumoconiosis. However, its acute human exposure has not been so far studied. We aimed at evaluating the putative mechanical, morphological, biochemical and inflammatory lung damage in mice acutely exposed to Tripoli dust. BALB/c mice were randomly assigned to 2 groups: In control group (CTRL, n=6) animals received intratracheally (i.t.) 0.9% NaCl (50µl), while Tripoli group (TRIP, n=15) received 20mg of Tripoli powder diluted in 50µL of saline i.t. The experiments were done 15 days later. TRIP mice showed higher pulmonary mechanical impedance, polymorphonuclear cells, TNF-α, IL1-ß and IL-6 than CTRL. TRIP presented granulomatous nodules containing collagenous fibers that occupied 35% of the lung tissue area. In conclusion, acute exposure to Tripoli dust triggered important lung damage in mice lungs that if found in human workers could trigger severe illness.

[Talc-induced pulmonary granulomas in drug addicts].

Among the diseases accompanied by granuloma formation in the lung, there is so-called granulomatosis developing in injection drug users who have been long injecting suspensions of oral medications containing talc and other water insoluble fillers. 102 deaths of chronic intravenous drug users were examined; 12 of whom showed pulmonary talc-induced granulomatosis. Their morphology was studied using polarized light microscopy. The main mechanisms of thanatogenesis in lethal cases within the first hours after intravenous injection of talc-containing oral medication suspensions are explained.

Delayed recruitment of lymphocytes into the lungs of CD30-deficient mice during aerogenic Mycobacterium avium infections.

CD30 is a member of the tumor necrosis factor-receptor superfamily, a group of receptors known to act as accessory molecules in the development of the immune response. Control and CD30-deficient mice were aerogenically infected with Mycobacterium avium. Although the mycobacterial loads in the lungs were similar in both strains of mice, CD30-deficient animals exhibited delayed structuring of pulmonary granulomas and reduced recruitment of lymphocytes throughout a 240 days period of infection. Discrete alterations in the chemokine network were detected in the CD30-deficient animals although they showed no clear relation to the deficient inflammatory response. Thus CD30/CD153 interactions are involved in lung immune-mediated inflammation.

11beta-hydroxysteroid dehydrogenases are regulated during the pulmonary granulomatous response to the mycobacterial glycolipid trehalose-6,6'-dimycolate.

OBJECTIVE: Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown. METHODS: One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6'-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology. RESULTS AND CONCLUSION: IL-6, IL-1alpha and TNF-alpha mRNA and protein peaked during the initiation of granuloma formation. Pulmonary corticosterone levels were elevated when the proinflammatory response was greatest, dropping to half of that upon the establishment of granuloma pathology on day 7. It is hypothesized that once corticosterone reaches the site of inflammation, the enzymes 11beta-hydroxysteroid dehydrogenases (11betaHSDs) can influence bioavailability by interconverting corticosterone and the inert metabolite 11-dehydrocorticosterone. RT-PCR demonstrated that pulmonary 11betaHSD type 1 mRNA decreased 4-fold and 11betaHSD type 2 (11betaHSD2) mRNA expression increased 2.5-fold on day 3 after injection, suggesting that corticosterone regulation in the lung, specifically the reduction of active corticosterone by 11betaHSD2, may influence the progression of granuloma formation in response to the mycobacterial glycolipid.

Radiology-Pathology Conference: pulmonary hyalinizing granuloma associated with lupus-like anticoagulant and Morvan's Syndrome.

Pulmonary hyalinizing granulomata are rare, noninfectious, fibrosing lesions of the lung, which can mimic metastatic disease radiographically. Their etiology is unknown, but they may be caused by an exaggerated immune response. We report the radiology, long clinical course, and pathology of a patient with pulmonary hyalinizing granuloma who presented with initially asymptomatic pulmonary nodules. Over a 10-year period, the patient developed multiple insidious autoimmune phenomena, including lupus anticoagulant, neuromyotonia, demyelinating sensorimotor polyneuropathy, and eventually, Morvan's syndrome. Such an association has not been previously published to our knowledge.

Pulmonary granulomatous inflammation: From sarcoidosis to tuberculosis.

Granulomatous inflammation of the lung is characterized by the recruitment and organization of activated macrophages and lymphocytes in discrete lesions laced in a network of matrix proteins. These lesions, termed granulomas, represent an important defense mechanism against infectious organisms such as fungi and mycobacteria, but also can be elicited by noninfectious agents. Occasionally, this inflammatory reaction can develop for unknown reasons, causing a systemic illness termed sarcoidosis. The mechanisms involved in granuloma formation in the lung have not been elucidated entirely. However, studies performed in animal models of granuloma formation and in humans suggest important roles for specific soluble mediators (eg, cytokines, chemokines) produced by monocytic cells. If uncontrolled, granulomatous inflammation leads to excessive tissue remodeling, causing fibrosis and/or cavitation as seen in tuberculosis. This review summarizes our current understanding of the factors involved in granuloma formation in the lung with particular attention to their role in sarcoidosis and tuberculosis.

Eosinophil recruitment in type-2 hypersensitivity pulmonary granulomas: source and contribution of monocyte chemotactic protein-3 (CCL7).

Monocyte chemotactic protein-3 (MCP-3/CCL7) has potent eosinophil chemoattractant properties. The present study determined its relative contribution to the formation of Th2 cytokine-mediated (type-2) eosinophil-rich interstitial lung granulomas induced by antigens of Schistosoma mansoni eggs. Both MCP-3 transcripts and protein levels were more strongly expressed in lungs with type-2 than with type-1 (mycobacterial antigen-elicited Th1-mediated) granulomas. In vivo treatment with neutralizing antibodies demonstrated that MCP-3 abrogated eosinophil accumulation in type-2 lesions by 40 to 50%. Immunohistochemical staining revealed that MCP-3 localized to vessels in or near granulomas suggesting that endothelial cells were an important in situ source of MCP-3. Maximal MCP-3 transcript expression was abrogated by anti-interleukin-4 treatment. Furthermore, cultured mouse lung endothelial cells displayed augmented MCP-3 production in response to interleukin-4. Together, these results suggest that MCP-3 contributes to a significant component of eosinophil recruitment in the type-2 interstitial granuloma formation and Th2 cytokines promote its production.

[Pulmonary hyalinizing granuloma: a case report and a review of the literature].

OBJECTIVE: To highlight the characteristics of pulmonary hyalinizing granuloma (PHG). METHOD: One patient with PHG confirmed by pathological assessment was presented and relevant literatures were reviewed. RESULTS: PHG is a rare disease characterized by multiple bilateral pulmonary nodules. Symptoms include cough, dyspnea, chest pain, hemoptysis, fever and fatigue. Histologically, the nodules consist of haphazard or whorled arrays of lamellar, keloid - like collagen. Evidence suggests that the nodules are the result of a chronic exaggerated immune response. CONCLUSIONS: PHG should be considered in patients showing multiple bilateral pulmonary nodules. The clinical course of PHG in most patients is benign. At present, there is no effective therapy.

The pathogenesis of beryllium-induced pulmonary granulomatosis. A scanning secondary ion analytical microscopy study.

Chronic granulomatous pneumonitis was induced in rats with beryllium to study the pathogenesis of that disease, by identifying and localizing the beryllium in histological sections of the pulmonary tissues. This was done with scanning secondary ion mass spectrometry (SIMS). Thus, our observations suggest that the route of the Be from the site of injection into the lung, passes first by the blood, through the vascular wall and into the surrounding pulmonary tissues where Be was phagocytized by macrophages. There resulted in acute vasculitis throughout the lung. It was noted that the granuloma were focal inflammatory sites, solely observed within the vascular wall, distributed along the course of the affected vessel. These findings raise the question as to whether pulmonary granulomatous lesions of other origins are also localized within the vascular wall.

Measurement of serum monocyte chemoattractant protein-1 and its clinical application for estimating the activity of granuloma formation in sarcoidosis.

BACKGROUND AND AIM OF THE WORK: The role of monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluids from sarcoidosis patients was previously reported. To study the role of MCP-1, we evaluated the serum MCP-1 and its clinical significance in sarcoidosis. METHODS: The serum MCP-1 level was measured in 47 patients with sarcoidosis and 10 normal healthy controls with the use of an enzyme-linked immunosorbent assay. The localization and mRNA expression of MCP-1 in sarcoid lymph nodes were evaluated by an immunohistochemical method using an anti-MCP-1 monoclonal antibody and an in situ hybridization technique to determine the cellular source(s) of MCP-1. RESULTS: Serum MCP-1 levels were significantly elevated in the sarcoidosis patients compared with the healthy controls (698.3 +/- 101.9 vs. less than 39 pg/ml, p < 0.001). A comparison of the patients' serum MCP-1 levels among standard radiographic stages revealed that the serum MCP-1 was significantly higher in early stages: stage 0 vs. III, and stage I vs. II. In addition, the serum MCP-1 levels were significantly correlated with the serum angiotensin converting enzyme levels (r = 0.539, p = 0.0006). MCP-1 expression was detected in macrophages peripheral to the epithelioid granuloma in sarcoid lymph nodes, by both immunohistochemistry and in situ hybridization. CONCLUSIONS: These data suggest that MCP-1 may be expressed by the macrophages in the granuloma throughout the body, and that the measurement of serum MCP-1 levels may have clinical value as an indicator in estimating the activity of granuloma formation throughout the body in sarcoidosis.

Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice.

Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.