Response Of Lung Tissue Research Articles

Expression of endothelin-1 in human broncho-epithelial and monocytic cell lines: Influence of tumor necrosis factor-α and dexamethasone

Abnormal endothelin-1 (ET-1) expression has been observed in bronchial asthma and systemic sclerosis with lung involvement. The purpose of this study was to analyze the synthesis of ET-1 in human airway epithelial cells and macrophages under basal conditions and after challenge with tumor necrosis factor-α (TNFα) or with the glucocorticoid dexamethasone. The ET-1 mRNA level and peptide release were measured in the broncho-epithelial cells BEAS-2B and the monocytic cell line U937. At baseline, U937 cells released low amounts of ET-1 peptide, whereas ET-1 was not detectable in BEAS-2B cells. After TNFα treatment, BEAS-2B cells, but not U937 cells, showed a significant increase in ET-1 expression, both at the mRNA and peptide levels. In contrast, dexamethasone elicited an increased amount of ET-1 peptide in U937 medium, but not in BEAS-2B cells. In this latter cell line, dexamethasone pretreatment was unable to inhibit the TNFα-induced expression. We conclude that response to TNFα and glucocorticoids is cell-type specific with respect to ET-1 production. The response of lung tissue to these agents in vivo is likely to be the overall balance of induction and inhibition in local microenvironments.

Lung Tissue Responses and Sites of Particle Retention Differ between Rats and Cynomolgus Monkeys Exposed Chronically to Diesel Exhaust and Coal Dust

Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dustexposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaustexposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures.

In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue

Influenza virus infection induces the local production of gamma interferon (IFN-gamma) by T cells and non-T cells in the respiratory tract. To elucidate the possible functions of this cytokine, the humoral and local cellular immune responses to influenza virus were studied in BALB/c mice with or without in vivo neutralization of IFN-gamma by using monoclonal antibodies. Neutralization of IFN-gamma led to a significant reduction in virus-specific titers of immunoglobulins G2a and G3 in serum but had little effect on other isotypes. Studies on cells isolated from the lung parenchyma itself revealed that at the height of the immune response the ability of these cells to produce cytokines after antigen or T-cell receptor/CD3 stimulation was not affected. Ex vivo cytolytic activity by lung parenchyma cells, which is induced by infection with this virus in normal mice, was also found to be undisturbed by this treatment, even though anti-IFN-gamma antibody activity was recovered from lung lavage samples and sera at all days studied. Surprisingly, in vivo neutralization of IFN-gamma led to a significant reduction in the magnitude of the cellular infiltrate in the lung tissue which followed infection, suggesting an involvement of IFN-gamma in the mechanisms that regulate increased leucocyte traffic in the inflamed lung parenchyma. This conclusion was supported by findings of differences between mock-treated and anti-IFN-gamma-treated mice in the number of CD8+ lung T cells expressing CD49d (alpha4-integrin) and CD62L at various times after influenza virus infection. This study therefore demonstrates that IFN-gamma affects the local cellular response in the respiratory tract as well as the systemic humoral response to influenza virus infection.

Leukotrienes in the pathogenesis of pulmonary blast injury.

Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast. The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure. The study was conducted on adult rabbits exposed to moderate blast overpressure (four pulmonary contusions characterized as confluent ecchymoses involving 30 to 60% of the lungs), generated in laboratory conditions. One group of experimental animals was treated with 5-lipoxygenase (5-LO) inhibitor, diethylcarbamazine (DEC, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast. The early posttraumatic period was observed (30 minutes after blast). Hemodynamic parameters (mean arterial pressure, heart rate, blood gases) as well as arterial plasma levels of conjugated dienes were observed. The myeloperoxidase activity, lipid peroxidation products levels, and water contents were measured in the lung tissue of injured rabbits. We observed that 5-LO inhibition reduced edema formation, accumulation of neutrophils, and generation of lipid peroxidation products in injured lungs. In this study, we demonstrated that treatment with DEC inhibits the increased systemic generation of conjugated dienes after blast injury. Although DEC exerts local antioxidant activity with beneficial effects on lung tissue, this 5-LO inhibitor intensifies the blast overpressure caused hemodynamic insufficiency.

Pulmonary Arteriole Hypertrophy in Broilers with Pulmonary Hypertension Syndrome (Ascites)

Two experiments were conducted to determine the effect of low ventilation or cool temperature environments on pulmonary arteriole hypertrophy. Male broilers were maintained under control or low ventilation conditions in Experiment 1, whereas male broiler breeder by-product chicks were exposed to cool temperature conditions in Experiment 2. Birds were randomly selected for histological evaluation of lung tissue in both experiments. In Experiment 1, birds that had pulmonary hypertension syndrome (PHS+) exhibited a greater degree of inflammation of lung tissue at 5 and 7 wk of age than controls or birds that did not have PHS (PHS-). These PHS+ birds also had higher numbers of cartilaginous osseous nodules at 3 and 7 wk of age than controls. Morphometric analyses revealed that PHS+ birds in Experiment 1 had a thicker medial layer associated with 100 to 200 μm diameter pulmonary arterioles at 7 wk of age, and 50 to 100 μ m arterioles at 3 and 7 wk of age than PHS- or control birds. In Experiment 2, PHS+ birds exhibited a thicker medial layer in pulmonary arterioles at 7 wk of age than did PHS- birds, but there were no differences in medial layer thickness at 5 wk of age nor were there differences in the degree of inflammation or amount of osseous nodule formation between PHS+ and PHS-birds at 5 and 7 wk of age. Thus, pulmonary arteriole hypertrophy was observed in birds having PHS in response to both low ventilation and cool temperature environments and this hypertrophy occurred with or without a coincident inflammatory response in lung tissue.

Partial characterization of the proliferative activity for fetal lung epithelial cells produced by silica-exposed alveolar macrophages

The proliferation of lung epithelial cells is a prominent feature of lung tissue response following silica-induced lung injury and alveolar macrophages are recognized as a major contributing cell to the lung inflammatory processes. In previous studies, a growth-promoting activity for fetal rat lung epithelial cells was observed in silicotic alveolar fluids and in supernatants from in vitro and in vivo silica-exposed alveolar macrophages. In the present work, the biological and physicochemical properties of the macrophage-derived growth-promoting activity for fetal lung epithelial cells were explored. Four peaks of growth-promoting activity for lung epithelial cells ranging from 32 to 7 kDa were found in both in vitro and in vivo silica-exposed macrophage supernatants. The investigations were coupled with biochemical treatments of the mitogenic peaks and blocking antibodies or antisera were used to specify further the nature of the proliferative activities. Among the established growth factors, alveolar macrophage-derived growth fractions had characteristics consistent with platelet-derived growth factor-, insulin-like growth factor 1-, and fibroblast growth factor-like molecules. The cytokine production following in vitro exposure, which reflects very early events in the pathogenesis of silicosis, was more strongly related to the high-molecular-weight PDGF-like molecules, whereas the cytokine production following in vivo exposure, which reflects later events in the pathogenesis of silicosis, was more influenced by intermediate-molecular-weight FGF- and IGF-like molecules.

Quantitative effect of combined chemotherapy and fractionated radiotherapy on the incidence of radiation-induced lung damage: A prospective clinical study

Purpose : The objective of this work was to assess the incidence of radiological changes compatible with radiation-induced lung damage as determined by computed tomography (CT), and subsequently calculate the dose effect factors (DEF) for specified chemotherapeutic regimens. Methods and Materials : A prospective, clinical study was conducted to determine the response of normal lung tissue to combined chemotherapy and radiotherapy. Radiation treatments were administered once daily, 5 days-per-week. Six clinical protocols were evaluated: ABVD (adriamycin, bleomycin, vincristine, and DTIC) followed by 35 Gy in 20 fractions; MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) followed by 35 Gy in 20; MOPP/ABVD followed by 35 Gy in 20; CAV (cyclophosphamide, adriamycin, and vincristine) followed by 25 Gy in 10; and 5-FU (5-fluorouracil) concurrent with either 50–52 Gy in 20–21 or 30–36 Gy in 10–15 fractions. CT examinations were taken before and at predetermined intervals following radiotherapy. CT evidence for the development of radiation-induced damage was defined as an increase in lung density within the irradiated volume. The radiation dose to lung was calculated using a CT-based algorithm to account for tissue inhomogeneities. Different fractionation schedules were converted using two isoeffect models, the estimated single dose (ED) and the normalized total dose (NTD). Results : A total of 102 patients were entered and 70 completed the study. Forty-two patients developed CT changes compatible with lung damage. The actuarial incidence of radiological pneumonitis was 71% for the ABVD, 49% for MOPP, 52% for MOPP/ABVD, 67% for CAV, 73% for 5-FU radical, and 58% for 5-FU palliative protocols. Depending on the isoeffect model selected and the method of analysis, the DEF was 1.11–1.14 for the ABVD, 0.96–0.97 for the MOPP, 0.96–1.02 for the MOPP/ABVD, 1.03–1.10 for the CAV, 0.74–0.79 for the 5-FU radical, and 0.94 for the 5-FU palliative protocols. Conclusion : Quantitative dose effect factors (DEF) were measured by comparing the incidences of CT-observed lung damage in patients receiving chemotherapy and radiotherapy to those receiving radiotherapy alone. The addition of ABVD or CAV appeared to reduce the tolerance of lung to radiation.

Toxicological investigations on silicon carbide. 1. Inhalation studies.

The question of lung damage as a result of exposure to silicon carbide (SiC) was investigated by inhalation experiments to obtain information on the qualitative response of lung tissue to the test substance (SiC). For comparison, quartz, kaolinite, and tempered clay dusts were used. The indices for the effects of the dusts studied were organ weights, numbers of bronchoalveolar cells, lung surfactant phospholipid concentrations including subfractions, and lung clearance. Exposure to the test samples was carried out according to the Essen inhalation model in two independent series. The results of the two series were similar: Compared with sham controls, exposure to SiC did not affect the indices studied. Even at a low dose (a quarter of the SiC dose) quartz gave pronounced deviations in all indices. In particular, an increase in granulocytes indicated toxic properties of the dust. The long term elimination of quartz from the lung was worse than that of SiC. The kaolinite and tempered clay dusts were intermediate between SiC and quartz based on several of the indices studied. It is concluded that SiC is deposited practically inert in the lung.

Conventional radiographic follow-up in the irradiated lung.

To highlight the different changes induced in lung tissues by various forms of radiotherapy (RT) according to tumor site and type. A retrospective analysis of the roentgenographic evaluation of and long-term follow-up data on 2375 patients who received RT for various intrathoracic and extrathoracic tumors at the National Cancer Institute of Milan. The iconographic patterns of post-RT changes, grouped by site and type of tumor and RT procedure and described in detail, afford deeper insight into a little-known area of lung pathology. These descriptions of common and uncommon patterns of the irradiated lung as they appear on conventional chest roentgenograms enable the radiologist and radiotherapist to assess exactly the response of tumor and lung tissues and to plan the most appropriate clinical follow-up.

A novel system for the culture of human lung: lung development and the response to injury.

Existing methods of fetal lung organ culture are complicated and require special skills. With the use of a polyester-based plastic sheet, we have developed a simpler human fetal lung organ culture that is viable for 6 wk. This novel method permits the study of growth and differentiation, pulmonary surfactant secretion, and the response of human lung tissue to injury in vitro. Lung tissues, obtained from human fetuses ranging in gestational age from 14 to 18 wk, were cultured on the polyester sheet in Dulbecco's modified Eagle medium supplemented with 15% fetal calf serum and gentamicin. Microscopic study of the fetal lung before culturing revealed round epithelial tubules, lined by glycogen-rich columnar cells and a thick cellular interstitium. After 1 wk in culture, morphological examination showed the development and expansion of alveolar saccules and thinning of the interstitium; type I and II pneumocytes as well as fibroblasts and myofibroblasts were present. Lipid analysis of the tissues, 2 wk after the initiation of the culture, demonstrated a high percentage of dipalmitoyl phosphatidylcholine characteristic of pulmonary surfactant. Treatment of the organ culture with asbestos fibers induced type II cell hyperplasia, increased numbers of collagen fiber bundles within the interstitium, and the accumulation of multi-lamellated surfactant material within the alveolar lumens. We conclude that this organ culture system is suitable for studying lung growth, development, and injury in human tissue.

On the impact of tissue inhomogeneity corrections in clinical thoracic radiation therapy

The magnitude and impact of the corrections required for calculated absorbed doses due to the presence of real anatomic inhomogeneities were studied in 100 “standard” clinical thoracic cases. Correction factor distributions were generated with the equivalent tissue-air ratio method. The correction factors at the point of target absorbed dose, the average within the high dose area, and the average and maximum within the irradiated lung tissue were determined. Results indicate that among patients undergoing similar treatment techniques and radiation energy, correction factors can vary greatly. The diversity in anatomy, geometry, and density emphasizes the need for patient-specific dose calculations if the appropriate accuracy is to be achieved. Even for simple parallel-opposed fields encompassing the mediastinal and bilateral lung regions, the correction at the point of target absorbed dose was found to be as much as 5 to 16% for photon energies between 60Co and 25 MV. The average correction factor within the high dose region was generally comparable in value. For beams that traverse the lungs obliquely, the correction factor at the point of target absorbed dose was as large as 1.21 with 25 MV photons. These values correlated linearly with the lung pathlength preceding the point. Within lung tissues, the corrections were often more dramatic. Using the dose response curve for normal lung tolerance, the clinical consequence of ignoring the increased dose to lung tissue can be predicted. For 100 patients, the use of uncorrected dose would result in an underestimation of the risk for radiological radiation pneumonitis by 7% on average and by as much as 19% maximally. These data suggest that whenever lung tissue and/or tumor response levels are critical, as is often the case for radical therapy, multi-center trials, and dose response determination, inhomogeneity corrections should be implemented.

Quantitative assessment of increased airway microvascular permeability to 125I-labelled plasma fibrinogen induced by platelet activating factor and bradykinin.

1. We have used 125I-labelled fibrinogen (I-FN) in experiments monitoring plasma extravasation from vessels within guinea-pig trachea and peripheral lung tissue in response to platelet activating factor (PAF) and bradykinin (BK). Retained tissue radioactivity derived from I-FN was detected by direct measurement and by autoradiography. 2. Both PAF and BK caused concentration-dependent increases in radioactivity in trachea and peripheral lung, with PAF being approximately 1000 times more potent than BK at both sites. On a wet weight basis, mean tracheal leakage responses to PAF and BK were approximately 6 times and 2 times greater respectively than those in peripheral lung. Furthermore, in trachea, the maximal response to PAF was nearly twice that to BK, although they were approximately equiactive in peripheral lung. The dipeptidyl carboxypeptidase inhibitor, enalapril (1 mg kg-1, i.v.), increased the potency of BK by approximately 40 fold. 3. In trachea, PAF (50 ng kg-1, i.v.)-induced leakage was selectively inhibited by the PAF receptor antagonist, WEB 2086 (5-50 micrograms kg-1), while responses to BK (50 micrograms kg-1, i.v.) were selectively inhibited by the BK2 receptor antagonist NPC 349 (0.5-1 mg kg-1). Neither PAF nor BK-induced leakage were significantly altered by pretreatment with the histamine H1-receptor antagonists mepyramine (10 micrograms kg-1) or ketotifen (50 micrograms kg-1) or the leukotriene receptor antagonist SKF 104353. These data indicate that both agonists caused direct, specific receptor operated increases in tracheal vascular permeability to plasma macromolecules.The alpha/beta1-adrenoceptor agonist adrenaline (100 pgkg-1) caused modest inhibition of leakage induced by BK, but not of the leakage response to PAF.4. Peripheral airway leakage responses to both PAF and BK were also detected by light microscopic autoradiography in paraffin-embedded tissue sections. This was possible since a significant amount of extravasated I-FN was apparently precipitated and fixed in the extravascular space as 125-labelled fibrin. Autoradiograms showed that both agonists caused increases in peripheral bronchial circulation microvascular permeability to I-FN. No evidence for leakage in alveolar wall capillaries or in pulmonary blood vessels was observed. Quantitation of such autoradiographic data will allow a comprehensive evaluation of the effects of putative asthma mediators on microvascular permeability throughout the respiratory tree.

Pulmonary microsomal alterations following short-term low level inhalation of p-xylene in rats

Rats exposed to 300 ppm para-xylene vapor for 1,3 or 5 days, 6 h/day, exhibited alterations in pulmonary microsomal membrane structural and metabolic parameters. Following 1 day of exposure, conjugated diene levels were elevated while total phospholipid levels, P-450 content, benzyloxyresorufin O-dealkylase activity and 2-aminofluorene N-hydroxylase activity were decreased. Core and leaflet membrane fluidity, ethoxyresorufin O-deethylase activity and aryl hydrocarbon hydroxylase (AHH) activity were unchanged at this time. Altered parameters began to return to control values by day 3 of exposure except for 2-aminofluorene N-hydroxylase activity, which remained decreased throughout the time course, and core membrane fluidity which was increased following 3 days of exposure. After 5 days of exposure, all parameters returned to control levels with the exception of AHH activity which was increased 41% at this time. Extracellular surfactant levels were also decreased by 1 and 3 days of exposure but returned to control values after 5 days. Initial pulmonary alterations produced by low level p-xylene exposure may be mediated by a peroxidative process. The initial damage triggers an adaptive response in lung tissue which possibly involves enzyme induction and/or cell proliferation. The increase in AHH activity after 5 days of exposure could have important consequences on the metabolism of co-administered xenobiotics.

The American Lung Fluke, Paragonimus kellicotti, in a Cat Model

Twenty-four specific-pathogen-free domestic cats were infected orally with from 2 to 30 Paragonimus kellicotti metacercariae and followed for 2-61 wk. Following infection by metacercarial cysts dissected from crayfish, the lungs of the cats undergo changes of intense eosinophilic pneumonia, granulomatous pneumonitis, squamous epithelial-lined cyst formation of bronchogenic origin, and finally (late in infection) partial resolution of the host response. Bronchograms and mechanical probing illustrate the patency of cyst communication with bronchi. The modulation of the host response and adaptive changes in the host lung tissue are seen late in infection and have previously been unreported or underemphasized. These adaptive responses may account for the number of asymptomatic cases accidentally found in veterinary patients and the difficulty in prompt and proper diagnosis in human cases.

Effects of steroid hormones pretreatment on isoprenaline-induced cyclic adenosine 3′,5′-monophosphate in rat lung

1. 1. Steroid hormones have been shown to regulate the concentration of adrenergic and muscarinic receptors in many tissues. 2. 2. The cyclic adenosine 3′,5′-monophosphate (cAMP) content in rat lung tissues in response to either dexamethasone, corticosterone, deoxycorticosterone or progesterone for 7 days were measured following intraperitoneal injection of isoprenaline just before sacrificed. 3. 3. There was a significant increase in cAMP level ( P < 0.001) in dexamethasone and corticosteronetreated rats compared to controls that received isoprenaline alone. 4. 4. Pretreatment with deoxycorticosterone and progesterone suppressed the increase in cAMP in response to isoprenaline. 5. 5. The effect of glucocorticoids in causing bronchodilatation in asthmatic patients is partly due to the restoration of adenyl cyclase responsiveness to beta-agonist.

Biochemical basis of ozone toxicity

Ozone (O 3) is the major oxidant of photochemical smog. Its biological effect is attributed to its stability to cause oxidation or peroxidation of biomolecules directly and/or via free radical reactions. A sequence of events may included lipid peroxidation and loss of functional groups of enzymes, alteration of membrane permeability, and cell injury or death. An acute exposure to O 3 causes lung injury involving the ciliated cell in the airways and the type 1 epithelial cells in the alveolar region. The effects are particularly localized at the junction of terminal bronchioles and alveolar ducts, as evident from a loss of cells and accumulation of inflammatory cells. In a typical short-term exposure the lung tissue response is biphasic: an initial injury-phase characterized by cell damage and loss of enzyme activities, followed by a repair-phase associated with increased metabolic activities, which coincide with a proliferation of metabolically active cells, for example, the alveolar type 2 cells and the bronchiolar Clara cells. A chronic exposure to O 3 can cause or exacerbate lung diseases, including perhaps an increased lung tumor incidence in susceptible animal models. Ozone exposure also causes extrapulmonary effect involving the blood, spleen, central nervous system, and other organs. A combination of O 3 and NO 2, both of which occur in photochemical smog, can produce effects which may be additive or synergistic. A synergistic lung injury occurs possibly due to a formation of more powerful radicals and chemical intermediates. Dietary antioxidants, for example, vitamin E, vitamin C, and selenium, can offer a protection against O 3 effects.

Alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice.

A single intracheal dose of liposome-encapsuled dichloro-methylene-diphosphonate resulted in the elimination of alveolar macrophages (AM) from the lung, creating a model to study the in vivo role of AM in the pulmonary immune response. Using intratracheally administered trinitrophenyl-keyhole limpet hemocyanin (TNP-KLH), the kinetics of the response, the location and number of TNP-specific antibody-forming cells, and the different Ig classes of the antibodies produced were studied in AM-depleted animals. The results show that AM elimination has a dramatic effect on the pulmonary immune responses against TNP-KLH. An increase in APC in lung-associated lymph nodes and a prolongation of the response is found, as well as an introduction of APC in lung tissue. In both experimental groups, the majority of the TNP-specific antibodies produced was IgG, followed by IgA and IgE, while very few IgM antibodies could be detected. We conclude from these results that AM are likely to play a role in controlling the pulmonary immune response in a suppressive way, thereby limiting the possible damage caused by severe immune responses in lung tissue.

Expression of la by Murine Alveolar Macrophages Is Upregulated during the Evolution of a Specific Immune Response in Pulmonary Parenchyma

These studies were performed to test the hypothesis that the evolution of a specific immune response in lung parenchyma upregulates the expression of Ia on surface membranes of murine alveolar macrophages. A secondary antibody-forming cell response to sheep erythrocytes was generated in lung parenchyma by intratracheal antigen challenge of systemically primed mice. During the immune response, alveolar macrophages were retrieved by bronchoalveolar lavage, and the percentages and total numbers of Ia-positive macrophages were measured by indirect immunofluorescence. The expression of Ia on surface membranes of lavaged alveolar macrophages increased in association with the generation of antibody-forming cell responses in lung tissue. This increase in Ia expression was antigen specific; intratracheal challenge with noncrossreacting antigen did not increase Ia expression. Nonspecific inflammation of the lung, induced by intratracheal hydrochloric acid, elicited increases in total numbers of macrophages that were similar in magnitude to those induced by specific immune responses, but increased Ia expression only modestly. In unprimed mice, intratracheal antigen challenge did not increase Ia expression by alveolar macrophages unless the mice had received immune splenocytes by adoptive transfer at the time of challenge. The results show that the generation of a specific immune response in pulmonary parenchyma upregulates the expression of Ia by murine alveolar macrophages in vivo and suggest that the accumulation of antigen-reactive lymphocytes in the lung plays an important role in this upregulation.

Lung inflammation: normal host defense or a complication of some diseases?

The inflammatory response in lung tissue is an important part of host defense that aids in removing microorganisms or particles that have reached the distal airways and alveolar surface. It augments the usual function of alveolar macrophages, immunoglobulins, and other defense mechanisms such as mucociliary clearance. However, excessive or poorly regulated inflammation can be destructive of tissue, thus contributing to many disease processes that can lead to fibrosis and impaired gas exchange. Several examples of diseases that feature inflammation as part of their pathophysiology have been selected for this review; i.e. asthma (especially examining the late-phase reaction that involves PMNs), chronic bronchitis (in which irritants and bacterial products may stimulate mucus secretion and inflammatory cells), interstitial lung diseases (IPF may disclose PMNs but sarcoidosis and hypersensitivity pneumonitis feature collections of activated lymphocytes), and acute lung injury leading to adult respiratory distress syndrome (PMNs and their breakdown products and enzymes incite local destruction of alveolar tissue). In preparation for these disease examples, a thorough review of the normal interactions between alveolar macrophages, various opsonins, complement and chemotactic factors, and the responsiveness of PMNs is given first.

Asbestos exposure dose-bronchoalveolar milieu response in asbestos workers and the sheep model: evidences of a threshold for chrysotile-induced fibrosis.

Epidemiological studies of asbestos workers have proposed a linear dose-response relationship between asbestos cumulative exposure indices and the incidence of asbestos-related lung diseases. However, for chrysotile, several studies have not observed such a linear relationship in low exposure workers. To further study the relationship of chrysotile exposure dose - lung tissue response, we designed in the sheep model one experiment of one exposure at variable intensity and one experiment with variable rates of individual exposures. In the first study, 6 groups of 6 sheep were exposed to either 0, 1, 10, 25, 50 or 100 mg chrysotile in 100 ml saline and lung lavage analyses carried out at day 0, 12, 24, 40 and 60 after. Histopathology was done at day 60. In the second experiment, 4 groups of 12 sheep were exposed to 100 ml saline every week or every two weeks, 100 mg chrysotile in 100 ml saline every week or every two weeks. In the second experiment, lung damage was assessed by changes in vital capacity (VC), lung compliance (Cst) and profusion of chest radiographic opacities (PO). On BAL in the control sheep, there were small and transient early increases in total cells/ml, macrophages/ml, neutrophils/ml, lactate dehydrogenase (LDH)/ml, alkaline phosphatase (AK)/ml, beta-glucuronidase (beta G)/ml and procollagen lll/ml. In the 1, 10, 25, and 50 mg asbestos sheep groups, there were no significant differences. However, in the 100 mg asbestos sheep, there were significant sustained increases in total cells/ml (3-6 times controls), macrophages/ml (2-6 times controls), neutrophils/ml (60-600 times controls), LDH/ml (5-10 times controls), AK/ml (1.5-2 times controls), beta G/ml (3-5 times controls), procollagen lll/ml (2 times controls) and IgG (1.5-3 times controls). These data were correlated with histopathological findings. In the sheep exposed weekly to chrysotile, significant changes in VC, Cst and PO occurred at mean cumulative exposure dose of 1.2 g whereas in the sheep exposed every 2 weeks, similar changes in VC, Cst and PO occurred at the cumulative exposure dose of 3.6 g (P less than 0.05). In conclusion, our data suggest that there is a threshold for chrysotile-induced fibrosis. This level cannot be considered adequately in term of cumulative exposure dose but must take into account intensity and rate of individual exposures.