Heterogeneity of mononuclear phagocytes in interstitial lung diseases

Interstitial lung diseases are a heterogeneous group of illnesses with different pathogeneses. In interstitial lung diseases there often is an increased influx of cells from the peripheral blood (PB) to the interstitium and alveoli. Besides the increase in total cell numbers, often marked shifts in the cell populations occur. This thesis describes the immunophenotype of the cells involved in three types of interstitial lung diseases, namely sarcoidosis, idiopathic pulmonary fibrosis (IPF) and extrinsic allergic alveolitis (EM). Emphasis is put on monocytic cells and macrophages. The cell surface markers of monocytes and macrophages as well as the immunophenotype of cultured purified monocytes have been studied. In addition surface antigens of cells from PB and bronchoalveolar lavage (BAL) fluid have been studied in the forementioned interstitial lung disease

Lung dendritic cells and host immunity to infection

The lung is a portal of entry for numerous microbial pathogens, against which evolution has created an adequate innate and adaptive immune response. Dendritic cells (DCs) are central to the integration of innate and specific immunity. These cells are located within the epithelium and interstitium of the lung where they are influenced by the innate immune system. Upon recognition and internalization of microbial antigens, DCs migrate to the draining lymph nodes of the lung to initiate the specific cellular and humoral immune response. By their capacity to integrate stimuli derived from the pathogen, the host and the environment, they are specialized to induce a protective immune response while at the same time avoiding damage to the host. It is becoming increasingly clear that dendritic cells are involved in the induction of immunity to viruses, bacteria, mycobacteria and fungi. Some pathogens subvert the function of dendritic cells to escape immune recognition. Not surprisingly, if dendritic cell function fails, the consequence for the host is immunodeficiency

Cyclic AMP enhancing drugs modulate eicosanoid release from human alveolar macrophages

The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control-respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55–93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 106 cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3–4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions

Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma

Asthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose at 20% fall of baseline forced expiratory volume in 1 s (FEV1), but also a plateau (P) representing the maximal narrowing response in terms of percent change in FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling dose). In the baseline condition, the specific airway conductance (sGaw) may be considered closely related to airway lumen diameter. In 20 nonsmoking asthmatic patients, methacholine dose-response curves were obtained, and a sigmoid model fit yielded the BHR indexes. Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used to recognize the total number of eosinophils and activated eosinophils, respectively. The number of activated eosinophils was significantly correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05), whereas weaker and nonsignificant correlations were found for dose at 20% fall of baseline FEV1 and the total number of eosinophils. We conclude that the number of activated eosinophils can be considered a marker of the inflammation-induced decrease of airway lumen diameter as represented by the plateau index and sGaw

Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients

STUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the augmented mechanical behavior of the lung. Therefore, we studied the interrelationships between indexes of BHR, on the one hand, and markers of lung parenchymal destruction, on the other. PATIENTS AND METHODS: COPD patients were selected by clinical symptoms, evidence of chronic, nonreversible airways obstruction, and BHR, which was defined as a provocative dose of a substance (histamine) causing a 20% fall in FEV(1) (PC(20)) of </= 8 mg/mL. BHR was subsequently studied by methacholine dose-response curves to which a sigmoid model was fitted for the estimation of plateau values and reactivity. Model fits of quasi-static lung pressure-volume (PV) curves yielded static lung compliance (Cstat), the exponential factor (KE) and elastic recoil at 90% of total lung capacity (P90TLC). Carbon monoxide (CO) transfer was measured with the standard single-breath method. RESULTS: Twenty-four patients were included in the study, and reliable PV data could be obtained from 19. The following mean values ( +/- SD) were taken: FEV(1), 65 +/- 12% of predicted; reversibility, 5.6 +/- 3.1% of predicted; the PC(20) for methacholine, 4.3 +/- 5.2 mg/mL; reactivity, 11.0 +/- 5.6% FEV(1)/doubling dose; plateau, 48.8 +/- 17.4% FEV(1); transfer factor, 76.7 +/- 17.9% of predicted; transfer coefficient for carbon monoxide (KCO), 85.9 +/- 22.6% of predicted; Cstat, 4.28 +/- 2.8 kPa; shape factor (KE), 1.9 +/- 1.5 kPa; and P90TLC, 1.1 +/- 0.8 kPa. We confirmed earlier reported relationships between Cstat, on the one hand, and KE (p < 0.0001), P90TLC (p = 0.0012), and KCO percent predicted (p = 0.006), on the other hand. The indexes of the methacholine provocation test were not related to any parameter of lung elasticity and CO transfer. CONCLUSION: BHR in COPD patients who smoke most probably is determined by airways pathology rather than by the augmented mechanical behavior caused by lung parenchymal destruction

Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1

PGD(2) is the major mediator released by mast cells during allergic responses, and it acts through two different receptors, the D prostanoid receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown that PGD(2) inhibits the migration of epidermal Langerhans cells to the skin draining lymph nodes (LNs) and affects the subsequent cutaneous inflammatory reaction. However, the role of PGD(2) in the pulmonary immune response remains unclear. Here, we show that the intratracheal instillation of FITC-OVA together with PGD(2) inhibits the migration of FITC(+) lung DC to draining LNs. This process is mimicked by the DP1 agonist BW245C, but not by the DP2 agonist DK-PGD(2). The ligation of DP1 inhibits the migration of FITC-OVA(+) DCs only temporarily, but still inhibits the proliferation of adoptively transferred, OVA-specific, CFSE-labeled, naive T cells in draining LNs. These T cells produced lower amounts of the T cell cytokines IL-4, IL-10, and IFN-gamma compared with T cells from mice that received FITC-OVA alone. Taken together, our data suggest that the activation of DP receptor by PGD(2) may represent a pathway to control airway DC migration and to limit the activation of T cells in the LNs under steady state conditions, possibly contributing to homeostasis in th