Inflammatory mediators of asthma: an update.

The respiratory epithelium maintains an effective antimicrobial environment to prevent colonization by microorganisms in inspired air. In addition to constitutively present host defenses which include antimicrobial peptides and proteins, the epithelial cells respond to the presence of microbes by the induction two complementary parts of an innate immune response. The first response is the increased production of antimicrobial agents, and the second is the induction of a signal network to recruit phagocytic cells to contain the infection. Inflammatory mediators released by the recruited cells as well as from the epithelium itself further induce the expression of the antimicrobial agents. The result is an effective prevention of microbial colonization. The epithelial cells recognize the pathogen-associated patterns on microbes by surface receptors such as CD14 and Toll-like receptors. Subsequent signal transduction pathways have been identified which result in the increased transcription of host defense response genes. Diseases such as cystic fibrosis, or environmental exposures such as the inhalation of air pollution particles, may create an environment that impairs the expression or activity of the host defenses in the airway. This can lead to increased susceptibility to airway infections.

The innate immune response of the respiratory epithelium

Tobacco smoke is believed to cause small airway disease and then chronic obstructive pulmonary disease (COPD), but the molecular mechanisms by which small airway obstruction occurs remain unknown. To study the gene expression levels of transforming growth factor (TGF)-beta1, a potent fibrogenic factor, in small airway epithelium from smokers and patients with COPD, we harvested highly pure samples of epithelial cells from small airways under direct vision by using an ultrathin bronchofiberscope BF-2.7T (outer diameter 2.7 mm with a biopsy channel of 0.8 mm in diameter). The expression levels of TGF-beta1 were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels of TGF-beta1 corrected by beta-actin transcripts were significantly higher in the smoking group and patients with COPD than those in nonsmokers (p < 0.01). Furthermore, among smokers and patients with COPD, TGF-beta1 mRNA levels correlated positively with the extent of smoking history (pack-years) and the degree of small airway obstruction as assessed by measurements of flow-volume curves. Immunocytochemistry of the cells demonstrated more intense stainings for TGF-beta1 in samples from smokers and patients with COPD than from nonsmokers. Spontaneously released immunoreactive TGF-beta1 levels from cultured epithelial cells were more elevated in subjects with a history of smoking and patients with COPD than in nonsmokers. Our study showed a close link between smoking and expression of TGF-beta1 in small airways. Our results also suggested that small airway epithelial cells might be involved in obstructive changes found in smokers and patients with COPD.

Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD).

Radiation pneumonitis and subsequent radiation pulmonary fibrosis are the two main dose-limiting factors when irradiating the thorax that can have severe implications for patients' quality of life. In this article, the current concepts about the pathogenetic mechanisms underlying radiation pneumonitis and fibrosis are presented. The clinical course of fibrosis, a postulated acute inflammatory stage, and a late fibrotic and irreversible stage are discussed. The interplay of cells and the wide variety of molecules orchestrating the immunologic response to radiation, their interactions with specific receptors, and the cascade of events they trigger are elucidated. Finally, the implications of this knowledge with respect to the therapeutic interventions are critically presented.

Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research.

Purpose: To investigate prospectively the utility of plasma transforming growth factor β1 (TGFβ1) as a marker for the development of symptomatic radiation pneumonitis. Materials and Methods: Seventy-three patients with lung cancer treated with curative intent are reported herein. Plasma TGFβ1 samples were obtained before, weekly during, and at each follow-up after radiation therapy (RT). TGFβ1 was extracted using an acid/ethanol method. An enzyme-linked immunosorbent assay was used to quantify plasma TGFβ1 concentrations. The TGFβ1 level at the end of RT was considered “normal” if it was both ≤ 7.5 ng/ml and less than the pretreatment value. All patients were followed for at least 6 months, unless symptomatic pneumonitis developed sooner. Pneumonitis was defined by National Cancer Institute (NCI) common toxicity criteria. Results: Fifteen of the 73 patients (21%) developed symptomatic pneumonitis and the remaining 58 (79%) did not. A normal plasma TGFβ1 by the end of RT, as defined above, was more common in patients who did not develop pneumonitis. A return of the plasma TGFβ1 to normal accurately identified patients who would not develop pneumonitis with both a sensitivity and positive predictive value of 90%. Conclusion: Plasma TGFβ1 levels appear to be a useful means to identify patients at low risk for the development of pneumonitis from thoracic RT. Thus, monitoring of plasma TGFβ1 levels may identify candidates for dose escalation studies in the treatment of lung cancer.

Plasma transforming growth factor β1 as a predictor of radiation pneumonitis

The ability of airway epithelial cells to produce transforming growth factor-beta (TGF-beta) may be an important mechanism for the control of growth, differentiation, and repair of the airway epithelium. To determine whether airway epithelial cells are capable of producing TGF-beta, we examined primary cultures of bovine bronchial epithelial cells. Using a bioassay, TGF-beta activity was detected readily in media conditioned by bovine bronchial epithelial cells. Neutralizing antisera to TGF-beta 1 and TGF-beta 2 were used to demonstrate that the majority of the activity was of the TGF-beta 2 isoform. Interestingly, some of the TGF-beta activity was present in the conditioned media as "active" TGF-beta, not requiring acid activation. The production of TGF-beta was variable, depending on cell density and the presence of retinoic acid. The presence of endogenously produced active TGF-beta in the culture media was shown to modulate the behavior of the cell cultures as evidenced by the effects of TGF-beta-neutralizing antisera on cell size and fibronectin production. Our results suggest that active TGF-beta produced by airway epithelial cells may function in an autocrine or paracrine manner to modulate epithelial cell behavior.

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Angie Rizzino

Papers

Spontaneous production of transforming growth factor-beta 2 by primary cultures of bronchial epithelial cells. Effects on cell behavior in vitro.