Causation between white blood cells and lung disorders confirmed

February 12, 2003

Bethesda, MD - Asthma affects five million children in the United States. This common chronic inflammatory condition of the bronchial airways causes the airways to become over-reactive, thus producing increased mucus, mucosal swelling and muscle contraction. The result can consist of airway obstruction, chest tightness, coughing and wheezing. If severe, this can cause severe shortness of breath and low blood oxygen. There is no cure for asthma and other deadly pulmonary disorders. But a new study offers revealing clues on why such disorders may develop - and the roles of key cells in the formation of the disease.

Background
For more than a century, researchers have examined the role of eosinophils, a type of white blood cells that accumulate wherever allergic reactions like those in asthma take place. Their natural role is to defend the body against parasites. At best, it is believed that asthma occurs following a malfunction of our protective mechanism against parasites. At worst, several studies with mouse models that correlate pulmonary eosinophilia with lung dysfunction fail to articulate eosinophil effector functions. This has led to recent questioning of the role of these white blood cells in allergic respiratory disease.

Attempts to define a specific causative relationship between eosinophils and the onset/progression of pulmonary pathologies (e.g., mucus overproduction and airway hyperresponsiveness (AHR) as found in asthma) in a mouse have been indecisive and in some cases suggest that linkage does not occur. On the other hand, data found suggest that eosinophils are linked to allergen-induced pulmonary disorders that arise from manipulation of interleukin-5 (IL-5), a cytokine derived from T lymphocytes that causes activation of B lymphocytes and differentiation of eosinophils.

Past research relied on the premise that IL-5 activities in the mouse are limited to increasing the number and survival effects on eosinophils, activities that elicit B cell maturation, and potential agonist effects directly on airway smooth muscle. However, because ovalbumin (OVA)-induced pulmonary diseases are not diminished in B cell-deficient mice, the loss of pulmonary pathologies in IL-5-deficient animals has been assumed to be a consequence of IL-5-mediated effects on eosinophils alone.

In an attempt to avoid the effects of neutralizing IL-5, eosinophils were removed in the lungs of allergen-sensitized/challenged mice through using CCR3, a chemokine receptor whose principal ligands (i.e., eotaxin -1 and -2) are potent chemoattractants, displaying a unique specificity for eosinophils.

The authors of "Ablation Of Eosinophils Leads To A Reduction Of Allergen-Induced Pulmonary Pathology" are J. Paul Justice, Michael T. Borchers, Jeffrey R. Crosby, Edith M. Hines, Sergei I. Ochkur, Michael P. McGarry, Nancy A. Lee, James J. Lee, and Huahao H. Shen, all from the Mayo Clinic, Scottsdale, AZ (Note: Dr. Shen is also affiliated with the Second Hospital, Zhejiang University College of Medicine, HangZhou, People's Republic of China). Their findings are in the January 2003 edition of the American Journal of Physiology--Lung Cellular and Molecular Physiology.

Methodology
The goal of this methodology was to abolish eosinophils from the airway lumen of OVA-sensitized/challenged mice and reduces the perivascular/peribronchial eosinophilia to levels indistinguishable from naive saline-challenged animals. Concurrent administration [through the peritoneal cavity (systemic) and as an aerosol to the lung (local)] of a rat anti-mouse CCR3 monoclonal antibody resulted in the abolition of eosinophils from the lung such that the airway lumen was essentially devoid of eosinophils. This procedure caused perivascular/peribronchial eosinophil numbers to be reduced to levels indistinguishable from saline-challenged animals.

Results
This antibody-mediated depletion was not accompanied by effects on any other leukocyte population, including, but not limited to, T cells and mast cells/basophils. In addition, no effects were observed on other underlying allergic inflammatory responses in OVA-treated mice, including OVA-specific immunoglobulin production as well as T cell-dependent elaboration of Th2 cytokines. The removal of virtually all pulmonary eosinophils in OVA-treated mice (i.e., without concurrent effects on T cell activities) resulted in a significant decrease in mucus accumulation and abolished allergen-induced AHR.

Conclusions
The finding in this study that eosinophils are required for allergen-induced pulmonary pathologies in the mouse provides evidence of a direct causative relationship between the white blood cell and the lung disorder. Moreover, the data support an expanded view of eosinophil activities in the lung and suggest that potential interactions with T cells are underlying mechanisms leading to allergic respiratory inflammation and lung dysfunction.
-end-
Source: January 2003 edition of the American Journal of Physiology--Lung Cellular and Molecular Physiology.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

American Physiological Society

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