PubMed Health⌕ Search

Biomedical subjects

R K Kumar

Publications and source records attributed to R K Kumar.

At least 73 records · Page 4Linked to original sources
PubMed1996

Epidermal growth factor-like molecular species in normal bronchoalveolar lavage fluid.

Normal bronchoalveolar lavage fluid (BALF) contains mitogenic activity for fibroblasts and type 2 pneumocytes. A number of growth factors that might contribute to this activity have been identified in BALF. We found that a molecule or molecules able to bind to epidermal growth factor (EGF) receptors on mouse lung fibroblasts were present in normal mouse BALF and could be blocked by an antiserum to mouse EGF. Receptor binding was partially blocked by preincubation with heparin, indicating a relationship to the heparin-binding subgroup of EGF-like growth factors. Heparin markedly enhanced the mitogenic activity of BALF for fibroblasts, but we were unable to establish whether the EGF-like molecule contributed to this activity. Immunoblotting using the anti-EGF serum identified a protein of M(r) 88,000 in concentrated BALF. The cellular source and physiological role of this growth factor merit further investigation.

Animals↗
PubMed1996

Epithelial cell-derived transforming growth factor-beta in bleomycin-induced pulmonary injury.

We have investigated whether enhanced secretion of transforming growth factor-beta (TGF-beta) by distal respiratory epithelial cells was associated with the development of bleomycin-induced pulmonary fibrosis. Type 2 pneumocyte-enriched preparations of bronchioloalveolar epithelial cells from normal mouse lung tissue released latent TGF-beta when cultured in serum-free medium. TGF-beta in culture supernatants could be detected using a sensitive enzyme immunoassay which employed enzyme complex amplification as a reporter system, as well as by a radiolabelled receptor competition assay. Exposure to bleomycin and other potentially fibrogenic stimuli in vitro did not stimulate production of TGF-beta by the epithelial cells but release was enhanced by treatment of the cells with interferon-gamma. Type 2 pneumocyte-enriched cell preparations obtained following induction of a pulmonary inflammatory response by administration of intratracheal bleomycin to susceptible C57BL/6 mice did not demonstrate increased release of TGF-beta in culture. However, the concentration of TGF-beta in bronchoalveolar lavage (BAL) fluids was significantly elevated compared to controls at 1 and 2 weeks after bleomycin-induced injury in these mice. No such increase was detected in BAL fluids from BALB/c mice, which are resistant to the effects of bleomycin. These results provide no support for a pathogenetic role of alveolar epithelial cell-derived TGF-beta in bleomycin-induced pulmonary fibrosis. Nevertheless, elevated levels of TGF-beta in BAL fluids may provide a marker of the progression of pulmonary injury to fibrosis.

Animals↗
PubMed1996

Chemokines and T lymphocyte recruitment to lymph nodes in HIV infection.

Recruitment of T lymphocytes to lymph nodes in patients with HIV infection is critical to the pathogenesis of disease. Chemokines are a family of cytokines, which are potent regulators of leukocyte migration. We studied the leukocyte populations and expression of chemokines known to be active upon T cells in lymph nodes of four HIV infected patients and seven control subjects using in situ hybridization, immunohistochemistry, and FACS analysis. The HIV lymph nodes showed CD8+ T lymphocyte accumulation and strongly enhanced chemokine expression, notably for the CD8+ T cell chemoattractant, macrophage inflammatory protein (MIP)-1 alpha. Resident macrophages appeared to be a major cellular source of chemokines in the HIV nodes. RANTES expression was present in both HIV and control lymph nodes, suggesting a physiological role for this chemokine in T lymphocyte recirculation. Chemokines may be important determinants of T lymphocyte accumulation in lymphoid tissue of patients with HIV/AIDS.

Adult↗
PubMed1995

Messages and handshakes: cellular interactions in pulmonary fibrosis.

A better understanding of early cellular events following pulmonary injury may permit the identification of those patterns of response which are destined to progress to fibrosis. Interactions between inflammatory, fibroblastic and epithelial cells appear to play crucial roles in fibrogenesis. Intercellular communication may be via "messages" delivered by soluble mediators or "handshakes" at sites of cell-to-cell contact. In this review, we question the validity of some prevailing concepts about the importance of growth factor secretion by alveolar macrophages; examine the possible role of activated T-lymphocytes in regulating macrophage production of mediators; and hypothesise that whereas fibroblast proliferation may primarily be stimulated by macrophage-derived cytokines, accumulation of collagen may be regulated by growth factors expressed by injured alveolar epithelial cells.

Animals↗
PubMed1995

Experimental models in pulmonary pathology.

Because of the cellular complexity and spatial organization of the lung, investigation of the pathogenesis of human pulmonary diseases relies to a considerable extent upon the use of animal models. In this review, the author examines new models and new applications of existing models of pneumonia, asthma, emphysema, interstitial lung disease and neoplasms in laboratory mice and rats. Studies of such models may assist in the development of appropriate strategies for early diagnosis and intervention.

Animals↗
PubMed1994

DNA cleavage by Cu(II)-desferal: identification of C1'-hydroxylation as the initial event for DNA damage.

Desferal, a siderophore of microbial origin is the only drug currently used for clinical treatment of a genetic disorder, thalassemia. By using a combination of HPLC and 31P-NMR, it is demonstrated that the Cu complex of desferal cleaves DNA, the primary site of hydroxyl radical attack being the sugar C1' in the minor groove, which leads to production of 5-methylene furanone. While no C5'-oxidation was observed, a minor process involving C4'-attack accompanies the above cleavage path. The oxidative cleavage of DNA observed with CuDFO may have implications in the emerging applications of desferal as a drug delivery agent and an antimalarial.

Animals↗
PubMed1994

Epidermal growth factor-like activity in bronchoalveolar lavage fluid in experimental silicosis.

We investigated whether development of pulmonary fibrosis following inhalational exposure of mice to silica (quartz) dust was accompanied by enhanced secretion of activity resembling epidermal growth factor (EGF). Mitogenic activity for pulmonary fibroblasts was assessed in bronchoalveolar lavage fluid (BALF) using a serum-free bioassay. Activity in BALF from mice exposed to nonfibrogenic titanium dioxide dust was comparable to that in BALF from normal animals. In contrast, mitogenic activity was significantly increased at 6 and 12 weeks after inhalation of silica particles, coinciding with the appearance of collagenised lesions in the lung. BALF from mice exposed to silica 6 weeks previously had significantly higher concentrations of growth factor(s) able to bind to EGF receptors on pulmonary fibroblasts. In parallel, macrophages within inflammatory lesions in the airspaces acquired immunoreactivity for EGF. The presence of an increased concentration of EGF-like growth factor(s) in BALF might constitute a marker of particle-induced pulmonary fibrosis.

Animals↗
PubMed1994

Immunoenzymatic detection of collagen production by pulmonary fibroblasts in serum-free culture.

We have developed an improved assay for the production of collagen by fibroblasts. Early passage adult mouse lung fibroblasts, established and maintained in serum-free culture, were employed as the target cells. An enzyme immunoassay was used for detection of type I collagen deposited on the substratum, permitting adaptation of the technique to cultures in 96-well microplates. Approximately two-fold enhancement of collagen deposition was induced by exposure to a concentration of 3 ng/ml of transforming growth factor-beta 1 or of 100 ng/ml of insulin-like growth factor-1 for 48 hr.

Animals↗
PubMed1993

Pulmonary balloon valvotomy for severe valvular pulmonic stenosis with congestive heart failure beyond infancy.

Isolated valvular pulmonic stenosis (PS) in association with tricuspid regurgitation and congestive heart failure (CHF) is rarely encountered after infancy, and there is very little information available regarding the application of pulmonary balloon valvotomy (PBV) for this subset of patients. Since 1985, 10 patients (5 males, 5 females; mean age: 12.4 +/- 7.5 years, range 4-25 years) underwent PBV for severe valvular PS with CHF in our institution. All patients had associated tricuspid regurgitation and cardiomegaly. Before PBV, the mean peak systolic gradient across the right ventricular outflow was 131 +/- 36 mmHg and the mean right atrial pressure was 14.4 +/- 5.4 mmHg. Specific modifications in the PBV technique included the sequential use of progressively larger balloon catheters and the use of an extra stiff guidewire to support the dilatation assembly. One patient underwent PBV via the right internal jugular vein. Problems encountered during PBV included hypotension and bradycardia (2 patients) and respiratory arrest, which was transient in one patient, and prolonged and eventually fatal in one patient. A successful outcome was achieved in 8 patients (4 of these required 2 PBV attempts) with a final residual gradient of 40 mmHg or less, mean 28 +/- 7; range: 21-38 mmHg) and complete resolution of CHF. One patient has had no significant change in gradients and awaits repeat dilatation. Patients with isolated severe valvular PS with TR and CHF represent a relatively high risk group for PBV. A successful outcome is, however, feasible if a carefully planned and cautious approach is used.

Catheterization↗
PubMed1993

Determinants of immediate and follow-up results of pulmonary balloon valvuloplasty.

The data of 93 patients (age 11.4 +/- 9.4 years, range 8 months-56 years) who underwent pulmonary balloon valvuloplasty (PBV) for valvular pulmonic stenosis (PS) in our institution are reviewed. The patients were classified into three groups: Group I (34 patients) had a right ventricular (RV) to aortic systolic pressure ratio of < 1, Group II (39 patients) had suprasystemic RV systolic pressures, and Group III (20 patients) included patients with elevated mean right atrial (RA) pressures irrespective of the RV systolic pressures. The percentage drop in immediate postdilatation peak systolic gradients (PSG) and the follow-up PSG were similar in the three groups and were not influenced by any predilatation patient characteristics. A balloon-annulus ratio < 1 predicted a poorer follow-up outcome. Nine patients, eight of Group III and one of Group II, experienced difficult procedures requiring sequential use of progressively larger balloon catheters. Eleven patients, six of Group II and five of Group III, experienced procedure-related events (hypotension, bradycardia/asystole, hypoxia, apnea, tachyarrhythmias, and seizures) and one patient (Group II) died. Although changes in immediate and follow-up gradients after PBV are not influenced by the severity of PS, difficult procedures and procedure-related events are particularly common in patients with severe PS and elevated RA pressures. A cautious and planned approach is therefore indicated in these patients.

Adolescent↗
PubMed1993

Pulmonary inflammation and fibrosis following subacute inhalational exposure to silica: determinants of progression.

To evaluate components of the pulmonary cellular response to inhaled silica that might be determinants of progression to fibrosis, we developed a model of the early stages of chronic human silicosis. Groups of mice were subacutely exposed either to alpha-quartz or to nonfibrogenic titanium dioxide dust as a control. Induction of lesions by inhaled silica was dependent upon the size distribution and dose of the particles. A novel observation was that low intensity exposure to silica evoked reversible inflammatory lesions that were characterized by focal aggregation of particle-laden alveolar macrophages near terminal airways. In contrast, higher intensity exposure elicited progressive pulmonary inflammation, including a significant perivascular influx of T-lymphocytes early in the response. The airspace inflammatory lesions exhibited a statistically significant decline in numerical density over time. Meanwhile, deposition of collagen was observed at perivascular locations, which were anatomically distinct from the initial foci of inflammation, and the numerical density of fibrotic lesions increased significantly with time. We speculate that this pattern of response might be related to alveolar clearance mechanisms being overwhelmed, followed by translocation and sequestration of particles in the interstitium, subsequently leading to T-lymphocyte recruitment and ultimately to the development of fibrosis.

Acute-Phase Reaction↗
PubMed1993

Secretion of epidermal growth factor-like molecular species by lung parenchymal macrophages: induction by interferon-gamma.

A population of cells enriched for pulmonary interstitial macrophages was obtained by differential adherence of lung parenchymal cells released by dissociation with trypsin. These cells secreted a molecule or molecules that bound to epidermal growth factor (EGF) receptors expressed on pulmonary fibroblasts. Secretion was reproducibly stimulated by exposure of the macrophages to interferon-gamma. Binding to EGF receptors could be blocked by a polyclonal antibody to EGF. It could also be partially blocked by incubation with heparin, suggesting that at least a component of the activity might be due to a member of the heparin-binding subgroup of the EGF family of growth factors. Because pulmonary fibrosis is consistently associated with inflammatory accumulation of activated T-lymphocytes, induction by interferon-gamma of growth factor secretion by macrophages could have pathogenetic importance. We speculate that similar cellular interactions may play a role in the progression of other chronic inflammatory lesions to fibrosis.

Animals↗
PubMed1992

Interstitial pulmonary macrophages produce platelet-derived growth factor that stimulates rat lung fibroblast proliferation in vitro.

Alveolar macrophages from humans and several animal species produce factors in vitro that modulate fibroblast growth and have been proposed as mediators of interstitial pulmonary fibrosis. Pulmonary interstitial macrophages (IMs) have not been studied previously in this regard. Pulmonary IMs were isolated from prelavaged rat lungs by enzymatic digestion of tissue and subsequent differential adherence of cells to culture dishes. The ability of IMs to release modulators of fibroblast growth into the culture medium was assessed by measuring [3H]thymidine incorporation into DNA and/or nuclear labeling of early-passage rat lung fibroblasts exposed to medium conditioned by IMs. The percentages of nuclei labeled in fibroblast cultures exposed to interstitial macrophage-conditioned medium (IMCM) alone did not significantly differ from that observed in controls, but fibroblasts exposed to IMCM supplemented with 2% platelet-poor plasma showed a 2.6-fold increase in labeling, indicating that IMCM contains predominantly "competence" growth factor activity. Similar results were obtained using purified human platelet-derived growth factor (PDGF). The level of growth factor activity released by IMs increased in cells that had phagocytized iron spheres during the culture period. In addition, fractionation of IMCM by high-performance liquid chromatography demonstrated most of the growth factor activity at a relative molecular mass of about 35 kd. Subsequent quantitative analysis of the fractions by an enzyme immunoassay for PDGF demonstrated that IMCM contains a homologue of human PDGF. These results show that IMs are capable of producing a PDGF-like growth factor for autologous fibroblasts and that release of this factor is enhanced by exposure to an insoluble inorganic particle. Because PDGF is a potent growth factor for fibroblasts and is released by IMs, it is essential to ask in future studies whether this or similar macrophage products play a significant role in mediating fibroblast proliferation in vivo.

Animals↗