Regional Heterogeneity in Murine Lung Fibroblasts from Normal Mice or Mice Exposed Once to Cigarette Smoke

Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure

Well-differentiated Papillary Mesothelioma With Invasive Foci

Well-differentiated papillary mesotheliomas (WDPMs) are usually encountered as incidental findings in the peritoneal cavity in women. Most WDPMs are benign, and the histologic features that indicate a more aggressive course are controversial. We report 20 cases of WDPM, which contained invasive foci. Thirteen cases arose in the peritoneal cavity, 1 in a hernia sac, 3 in the pleural cavity, and 3 in hydroceles. The female:male ratio was 16:4, and age range was 7 to 74 years. Tumor was multifocal in 15 cases. Some tumors showed back-to-back papillae, a pattern mimicking invasion but discernible on pan-keratin stain as compressive crowding. True invasive patterns ranged from simple bland-appearing glands invading the stalks of the papillae to solid foci of invasive tumor of higher cytologic grade than the original WDPM. All 5 tested cases were negative for p16 deletion by fluorescence in situ hybridization, but 2/3 had abnormal karyotypes. Recurrences were seen in 8 patients, and in 4 multiple recurrences were documented. Of 16 patients with follow-up, 14 are alive from periods of 6 months to 6 years (average 3.5 y), and 2 have known recurrent disease. One patient died of disseminated tumor at 8 years but without histologic confirmation of the nature of the tumor. We conclude that WDPM with invasive foci in the papillae appear to be prone to multifocality and recurrence, but that they rarely give rise to life-threatening disease. We suggest that these lesions be called WDPM with invasive foci to alert clinicians to the possibility of recurrence

Controlled human exposures to ambient pollutant particles in susceptible populations

Epidemiologic studies have established an association between exposures to air pollution particles and human mortality and morbidity at concentrations of particles currently found in major metropolitan areas. The adverse effects of pollution particles are most prominent in susceptible subjects, including the elderly and patients with cardiopulmonary diseases. Controlled human exposure studies have been used to confirm the causal relationship between pollution particle exposure and adverse health effects. Earlier studies enrolled mostly young healthy subjects and have largely confirmed the capability of particles to cause adverse health effects shown in epidemiological studies. In the last few years, more studies involving susceptible populations have been published. These recent studies in susceptible populations, however, have shown that the adverse responses to particles appear diminished in these susceptible subjects compared to those in healthy subjects. The present paper reviewed and compared control human exposure studies to particles and sought to explain the "unexpected" response to particle exposure in these susceptible populations and make recommendations for future studies. We found that the causes for the discrepant results are likely multifactorial. Factors such as medications, the disease itself, genetic susceptibility, subject selection bias that is intrinsic to many controlled exposure studies and nonspecificity of study endpoints may explain part of the results. Future controlled exposure studies should select endpoints that are more closely related to the pathogenesis of the disease and reflect the severity of particle-induced health effects in the specific populations under investigation. Future studies should also attempt to control for medications and genetic susceptibility. Using a different study design, such as exposing subjects to filtered air and ambient levels of particles, and assessing the improvement in biological endpoints during filtered air exposure, may allow the inclusion of higher risk patients who are likely the main contributors to the increased particle-induced health effects in epidemiological studies

Acute exacerbation (acute lung injury of unknown cause) in UIP and tohere forms of fibrotic interstitial pneumonias.

Acute exacerbation of usual interstitial pneumonia (UIP) is a condition in which patients with UIP, and occasionally other forms of fibrotic interstitial lung disease, develop rapid respiratory failure, accompanied by extensive radiologic infiltrates. The pathologic features of this condition are ill-defined in the literature and the outcome is unclear. We report 12 such patients, 9 with underlying UIP, 2 with underlying fibrotic nonspecific interstitial pneumonia, and 1 with underlying chronic hypersensitivity pneumonitis, who underwent surgical lung biopsy for diagnosis. High-resolution computed tomography data were available in 11 cases and showed the presence of extensive bilateral ground-glass opacities, sometimes accompanied by focal consolidation, superimposed on underlying fibrosis. Three microscopic patterns of acute lung injury were seen: diffuse alveolar damage (DAD), organizing pneumonia (OP), and a pattern of numerous very large fibroblast foci superimposed on underlying fibrosis. After the biopsy, all patients were treated with steroids, in some instances accompanied by cyclophosphamide or azathioprine. Ten patients survived the acute episode and were discharged with survival times of 1 to 11 months; of these cases, 6 showed a pattern of OP or OP plus extensive fibroblast foci; 2 a pattern of extensive fibroblast foci only; and 2 a pattern of DAD. Both patients who died had histologic DAD. We conclude that acute exacerbation of UIP and other fibrotic lung diseases produces a variety of pathologic patterns on biopsy, and that patients with OP or extensive fibroblast foci as the acute pattern seem to do better than those with DAD. Our data also imply that survival (of the acute episode) may be better than the literature suggests