Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers-as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors.

Asthma is a common disorder that affects genders differently across the life span. Earlier in life, it is more common in boys. At puberty, asthma becomes more common and often more severe in girls and women. The effect of sex hormones on asthma incidence and its severity is difficult to differentiate from other asthma severity risk factors, such as racial background, socioeconomic factors, obesity, atopy, environmental exposure, and, in particular, lung aging. Recognizing gender-associated and age-associated differences is important to understanding the pathobiology of asthma and to providing effective education and personalized care for patients with asthma across the life course.

The prevalence of asthma is higher in women than men of reproductive age and almost half of all hospitalisations for asthma in women occur during the perimenstrual phase of the cycle. The mechanisms of premenstrual asthma (PMA) are unknown and a definition of PMA has not been clearly presented in the literature. The objective of this study was to determine the prevalence of PMA using a variety of definitions, to investigate the cycle-to-cycle variation in PMA, the effects of oral contraceptive use and the relationship between PMA and premenstrual symptoms. Premenopausal women with asthma (n = 28) were prospectively followed for at least 12 weeks over 2-4 consecutive menstrual cycles. Asthma symptoms, beta(2)-agonist and inhaled corticosteroid use and morning and evening peak expiratory flow were recorded daily. The following types of PMA definitions were investigated: self-reported PMA, increased symptoms, increased medication use, decreased peak flow or a combination of changes in symptoms, medication and peak flow. Changes of more than 20%, for at least 2 consecutive days of the luteal phase (last 14 days of the cycle prior to menstruation) compared to the early follicular phase average (first 7 days after menstruation) were considered PMA. Using a composite definition where subjects experienced increased symptoms and medication use with or without a change in peak flow, 16 subjects were classified as having PMA (57%), while 12 did not have PMA. Only 4 subjects (25%) had PMA in every cycle examined. Fifty-five percent of subjects who used oral contraceptives had PMA, while 59% of subjects who did not use oral contraceptives had PMA. Women who were defined PMA using the composite definition were more likely than those without PMA to experience a 20% decrease in peak flow during the luteal phase. There was no relationship between asthma symptoms and premenstrual symptoms on day 1 of the menstrual cycle in women with PMA. PMA resulting in increased symptoms and medication use occurred in 57% of subjects studied for 2-4 menstrual cycles. The use of oral contraceptives is not protective and further work is required to elucidate the mechanisms of PMA.

Perimenstrual asthma (PMA) has been documented in 30% to 40% of asthmatic women; the characteristics of PMA have also been well described. However, there have been few epidemiological investigations of PMA in practice. In this study, we analyzed PMA based on a questionnaire survey carried out in Japan and compared the results with those of studies reported previously.

For 8 weeks from September through October 2004, a questionnaire survey was administered to patients with bronchial asthma and their attending physicians. The questionnaire surveyed asthma control, asthma-related emergencies and satisfaction in daily life. The attending physicians were questioned about patient profiles and medications. All female patients who were menstruating during the survey period and who were known to have asthma exacerbation related to menstruation were allocated to the PMA group; those who were not were allocated to the non-PMA group.

The rate of PMA in female patients who were menstruating during the survey period was 11.3% in this study. Characteristic features of the PMA group (n = 54) included more severe disease, worsened disease control and more aggressive patient management, including increased oral corticosteroid use compared with the non-PMA group. The rates of emergency episodes in the PMA group were higher than in the non-PMA group. There was a significant increase in aspirin intolerant asthma (AIA, 25.5%) in the PMA group compared with the non-PMA group (8.4%).

Attention should be paid to the lack of knowledge regarding PMA in patients with asthma in actual clinical settings. The low rate of PMA reported in this study may be due to the study method using self-reports of PMA by patients without sufficient knowledge, and may not be an accurate representation of the actual incidence of the disease. The clinical similarity of PMA to AIA in this study may also provide a new insight into the mechanism of PMA.

Perimenstrual worsening of asthma has been documented in 30% to 40% of asthmatic women. This increase in symptoms has been backed up by increased health care use perimenstrually, as well as by cyclic variation in peak expiratory flows. The cause of perimenstrual asthma (PMA) remains unclear. Fluctuations in hormone levels, their ratios, or both are a plausible explanation but have not been demonstrated with any consistency. Influences of sex hormones on inflammation is an area of future research, as are hormone-induced changes in smooth muscle function and beta-adrenergic receptors, prostaglandin levels, and fluid retention in the bronchial mucosa. In the light of the high prevalence of PMA, it is difficult to understand why there has been no randomized controlled trial of hormone therapy. Nevertheless, several case reports have suggested beneficial effects of estrogens, progestins, and their combination. In light of these positive case reports, well-designed, double-blind studies of sufficient sample size should now be performed to give treatment of PMA an evidence base.

Premenstrual asthma (PMA) is a clinical picture with worsening of asthmatic symptoms and pulmonary functions in the late luteal phase of the menstrual cycle. The aim of this study was to evaluate the inflammatory changes in asthmatic women who complain of PMA. Forty asthmatic women attending our outpatient clinic were questioned about worsening of their asthma before menstruation. Eleven women (aged 17-40) who complained of PMA participated in the study. Subjects were asked to record peak expiratory flow rates, symptom scores, and beta-agonist use daily. After the first menses on the seventh day of their cycle, and before the onset of the next menstruation, on the 26+/-3rd day of the cycle, patients were evaluated with pulmonary function tests, methacholine challenge test, and fractionated exhaled nitric oxide (FE(NO)) levels. Eosinophils in peripheral blood and induced sputum were also evaluated. When comparing the two groups of results, the significant changes were in FENO levels, day-time symptom scores, and eosinophils in induced sputum (29.25 ppb/9.16 ppb p < 0.05, 1/0.45 p = 0.05, %6.63/%4.09 p < 0.01, respectively, before and after menstruation). These results show that PMA is not only a clinical picture with a decrease in airway calibre that can be related to the regulation of 2 receptors, but also a complex state with worsening of airway inflammation.

The exacerbation of asthma in the premenstrual period has long been of interest. Premenstrual asthma has been estimated to affect up to 40% of females with asthma, although the exact prevalence of this phenomenon is unclear as studies have involved small numbers in hospital clinics. Large-scale community-based studies are required to estimate its true prevalence. Researchers are slowly piecing together clues as to the aetiology and pathogenesis of the disorder. Female sex-steroid hormones play an important role but the exact mechanism is still unknown. Recent evidence suggests that increased airway hyperresponsiveness, an indicator of underlying airway inflammation, during the luteal phase of the menstrual cycle may account for premenstrual exacerbations. In addition, there is now evidence of impaired or altered beta2-adrenoceptor function and regulation in females with asthma, which may have a part to play. Accurate diagnosis is dependent on a detailed history and the demonstration of premenstrual dip in peak expiratory flow. Exacerbations in the majority of women will respond to the usual treatment of bronchial asthma. However, a few women will experience significant morbidity or treatment-related adverse effects. Case reports suggest that the combined oral contraceptive pill or gonadotrophin-releasing hormone analogues may be effective in these patients. This requires substantiation by randomised controlled trials.

Pharmacists should be aware of gender-based differences and menstrual cycle-related changes in six diseases: asthma, arthritis, migraine, diabetes, depression, and epilepsy. In general, women report symptoms of physical illness at higher rates, visit physicians more frequently, and make greater use of other health care services than men. Whereas reasons for these gender differences are not fully clear, a combination of biologic, physiologic, social, behavioral, psychologic, and cultural factors most likely contributes. A significant percentage of women with asthma, arthritis, migraine, diabetes, depression, or epilepsy experience worsening of their disease premenstrually. The mechanism is unknown, but is speculated to be multifactorial because of many endogenous and exogenous modulators and mediators of each disease. As part of general therapy for cycle-related exacerbations of any one of these disorders, patients should be encouraged to use a menstrual calendar to track signs and symptoms for two to three cycles; if cyclic trends are identified, the women should anticipate exacerbations and avoid triggering factors. Cyclic modulation with pharmacotherapy may be attempted. If unsuccessful, a trial of medical ovulation suppression with a gonadotropin-releasing hormone (GnRH) analog may be warranted. If that is successful, continuous therapy with a GnRH analog and steroid add-back therapy or less expensive alternatives may be effective. If pharmacotherapy is impractical, hysterectomy and bilateral oophorectomy with estrogen replacement therapy is a last resort. Gender differences and menstrual cycle-related changes are important areas for clinical and mechanistic research.

We examined the effects of estrogen on tumor necrosis factor alpha (TNF-alpha)-induced expression of intracellular adhesion molecule (ICAM-1) and vascular adhesion molecule (VCAM-1) in cultured human bronchial smooth muscle cells (BSMC). Experiments were performed in triplicate in T-75 tissue culture flasks containing normal human BSMC. Four experiments were carried out: untreated BSMC cells (control); TNF-alpha 1000 U/ml stimulation of BSMC; forskolin 5 microM before TNF-alpha stimulation of BSMC; and estradiol 30 microM before TNF-alpha stimulation of BSMC. Cyclic adenosine monophosphate was measured by a commercially available radioimmunoassay kit. Cell expression of ICAM-1 and VCAM-1 was quantified by flow cytometry Incubation of cells with TNF-alpha 1000 U/ml for 24 hours elicited a 27-fold increase in basal expression of ICAM-1 and a 2-fold increase in VCAM-1 (p>0.05). Incubation of BSMC with forskolin 5 microM, for 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 62% and VCAM-1 slightly by 17%. The BSMC incubated with estradiol 30 microM, 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 21%; VCAM-1 remained unchanged (p>0.05). We found a trend toward inhibition of TNF-alpha-stimulated ICAM-1 expression in cultured BSMC with pretreatment with estradiol. However, due to large variability within the cell culture model, statistical significance was not reached.

The etiology and treatment of premenstrual exacerbations of asthma (PMA) remain uncertain.

We investigated the role of cellular mediators released from inflammatory cells in the airflow limitation during PMA.

Serum levels of leukotriene (LT) B(4), LTC(4), platelet- activating factor, histamine, IL-1beta, IL-4, IL-5, IL-6, and GM-CSF were measured at different time points, first just before or during menstruation when the peak expiratory flow rate (PEFR) began to decrease precipitously and second during the menstrual midcycle week (days 10-16) when the PEFR returned to baseline values in patients with PMA and in age-matched asthma patients without PMA at the same intervals.

Serum levels of LTC(4) were significantly higher during exacerbations of asthma than after recovery (69.0 +/- 16.0 pg/mL vs 24.0 +/- 9.5 pg/mL, P <.05), whereas those of IL-1beta, IL-4, IL-5, IL-6, GM-CSF, histamine, LTB(4), and platelet-activating factor did not differ between 2 periods in 5 patients with PMA. In contrast, in 5 asthmatic patients without PMA serum levels of cellular mediators did not differ between corresponding periods. Oral administration of pranlukast, an LT receptor antagonist (225 mg twice daily), significantly reduced decreases in PEFR from the baseline values (110 +/- 21 L/min with pranlukast vs 233 +/- 20 L/min without pranlukast, P <.01) in association with an improvement of asthma symptom scores (6.5 +/- 1. 1 with pranlukast vs 9.8 +/- 0.7 without pranlukast, P <0.05) in 5 patients with PMA.

LTs are partly involved in the pathogenesis of PMA, and LT receptor antagonists may be useful for preventing airflow obstruction in patients with PMA.

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24 h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24 h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.

To characterize and compare premenstrual symptoms (mood, physical) throughout two menstrual cycles with and without estradiol administration, in women with premenstrual asthma (PMA), and to examine relationships between asthma symptoms versus premenstrual symptoms and pulmonary function versus premenstrual symptoms in these women.

Open-label, longitudinal, 9-week study (consisting of two complete menstrual cycles).

Clinical study at the University of Kentucky; data analysis at the University of British Columbia and Children's and Women's Health Centre of British Columbia.

Fourteen women (age 35.6 +/- 6.6 yrs) with mild to moderate asthma with a baseline ratio of forced expiratory volume in 1 second:forced vital capacity of 0.72 +/- 0.12.

Women were followed for two complete menstrual cycles. During the second complete cycle (i.e., cycle 3), they received estradiol 2 mg orally between days 23 and 28 (premenstrual).

Throughout both cycles 2 and 3, each subject recorded premenstrual symptom questionnaire scores (15 mood and physical symptoms, graded 0-3) every morning on awakening. Peak expiratory flow rate (PEFR) and visual analog scales of asthma symptoms (cough, wheezing, breathlessness, chest tightness) were recorded daily at the same time. Seven subjects showed a classic pattern of premenstrual symptoms. Four of the five subjects who complained of PMA symptoms at study enrollment also demonstrated this classic pattern of premenstrual symptoms. After estradiol administration, four women had lower symptom scores, eight had higher scores, and two had the same scores. Overall, estradiol had no significant effect on symptoms (mean area under the curve 18.9 +/- 14.8 day(-1) vs 20.3 +/- 14.8 day(-1), p>0.05). Ten subjects had significant relationships between asthma symptoms and premenstrual symptoms, whereas six had significant relationships between PEFR and premenstrual symptoms.

Exogenous estradiol administration had no significant effect on premenstrual symptoms in women with PMA. The lack of a significant effect allows for patient blinding in a placebo-controlled, crossover study of exogenous estradiol in PMA that is currently under way Clinical implications of relationships between asthma symptoms versus premenstrual symptoms and pulmonary function versus premenstrual symptoms may warrant further study.

The relationship between sex hormones and asthma has not been clarified. Studies have suggested a potential beneficial effect of exogenous sex hormones and/or contraceptive pills on asthma in premenopausal females whereas the data for postmenopausal females are inconsistent.

A 33-year-old woman suffering from asthma with premenstrual exacerbations had a stable course until she began taking oral contraceptives. At that time she experienced clinical deterioration of her asthma associated with decline of pulmonary function tests. No other precipitating factors were identified. After discontinuing the contraceptives, her condition returned to baseline.

We found only two reports of worsening of asthma related to hormonal therapy (estrogen in one case, contraceptive pills in the other) in premenopausal women. Our report, together with these observations, suggests that in some premenopausal women exogenous sex hormones and/or contraceptive pills may, contrary to expected, produce exacerbation of asthma.

Studies suggesting that 30% to 40% of asthmatic women report significant perimenstrual (late luteal phase) exacerbations of asthma are primarily retrospective, rely on subjective findings and do not demonstrate a consistent association between asthma and the menstrual cycle.

In this exploratory analysis, women with and without self-reported perimenstrual exacerbations of asthma (PMA) were examined prospectively to determine the association between asthma and the menstrual cycle and to characterize associated clinical factors.

Thirty-two adult asthmatic women with regular menstrual periods recorded daily asthma symptoms, medication use, and peak expiratory flow rate (PEFR) over six consecutive menstrual cycles, and underwent spirometry and methacholine bronchoprovocation during the luteal and follicular phases of 2 cycles.

Nine of 32 subjects (28.2%) reported PMA. Daily means of rescue medication use and AM peak flow computed for each perimenstrual day demonstrated significant non-parallelism of group profiles; subjects with PMA had increasing inhaled short acting beta 2-agonist use and decreasing AM peak flow rates during the perimenstrual interval. Luteal-follicular phase differences in FEV1 or methacholine bronchoprovocation between the groups were not detected. Subjects with PMA were older (P=.007), had longer duration of asthma (P=.039), and increased baseline asthma severity (P=.076) compared with subjects without PMA.

The findings of this study suggest that women with self-reported perimenstrual asthma demonstrate perimenstrual differences in rescue bronchodilator use and AM peak flow and appear to constitute a distinct subset of women with asthma who are older, have longer duration of asthma, and increased severity of asthma compared with women without self-reported perimenstrual asthma. These factors identify women who require close monitoring of their asthma during their menstrual cycles.

This study was conducted to determine the occurrence of menstrual-linked asthma (MLA) in India in 100 consecutive female asthmatics in the reproductive age group. The patients were required to respond to a questionnaire concerning the relationship between their asthma and the menstrual cycle. Twenty-three patients had subjective perception of deterioration in symptoms of asthma in relation to the menstrual cycle. Ten patients from both groups were also required to maintain a daily peak expiratory flow rate (PEFR) diary for 2 consecutive menstrual cycles. The mean total duration of illness in patients with MLA was significantly longer than in patients without cyclic exacerbation. Cough and breathlessness were also significantly more severe as was the disease. This was evidenced by the more frequent emergency room visits and hospitalizations in these patients. Menstrual-linked worsening of asthma was most common in the premenstrual week (17 patients), in 8 of these 17 patients, this phenomenon continued to occur during the menstrual week also. Interestingly, 1 patient complained of deterioration of asthma 2 days after menstruation was over. Such an observation is yet to be recorded. Fourteen patients reported an increase in symptoms with almost every cycle while 3 had worsening related to specific season only. Sixteen patients often required extra medication during the premenstrual and/or menstrual weeks. A significant association was also observed between severity of premenstrual syndrome and MLA. The mean PEFR values over 2 cycles revealed a significant fall in the morning as well as evening values in the premenstrual and menstrual weeks as compared to the midcycle week in patients with MLA. This fall was maximal in the premenstrual week. Such a fall was not observed in asthmatics without menstrual exacerbation of symptoms. MLA was detected in about a fourth of the female asthmatics in India and it appears to represent a more severe form of the disease. This study also documented that MLA was associated with an increase in airway resistance and was not simply due to an increased perception of symptoms during the premenstrual or menstrual weeks.

A postmenopausal woman with severe obstructive airways disease and bronchospasm developed increased airflow limitation with the reintroduction of estrogen therapy for osteoporosis. Discontinuation of the estrogen caused symptomatic improvement and decreased her corticosteroid requirement. Readministration of estrogen caused recrudescence of her symptoms and a decline in her peak expiratory flow rate and spirometric data, which reversed with withdrawal of the estrogen therapy. Bronchospasm during the luteal phase of the menstrual cycle is well known, but exacerbation of reactive airways disease with the administration of exogenous estrogen has not previously been reported; however, with the increasing practice of reintroducing estrogen in postmenopausal women to reduce the risk of symptomatic osteoporosis, other susceptible women may suffer clinically significant deterioration of their underlying pulmonary disease.

Investigations of premenstrual asthma (PMA) have been based on studies of asthmatics already aware of a deterioration of asthma premenstrually. Little is known, therefore, about relationships between the menstrual cycle and airway function in asthmatics who do not complain of PMA or in normal subjects. We investigated airway function in both of these groups for three or four consecutive menstrual cycles. Daily records of asthma symptoms and peak expiratory flow rates were maintained by 11 asthmatics and 29 normal control subjects. Standard spirometry and serum estradiol and progesterone levels were measured during the follicular, midluteal, and late luteal phases of the menstrual cycle. Airway reactivity to methacholine was tested during the follicular and luteal phases. The normal group showed no significant changes in symptoms, peak flow rates, spirometric parameters, or airway reactivity. Although the asthmatic group also demonstrated no significant changes in spirometry and airway reactivity, asthma symptoms (shortness-of-breath, cough, wheeze, and chest tightness) deteriorated significantly (p less than 0.001) from the follicular to the luteal phase, as did the morning peak flows of the asthmatics (p = 0.045). Airway function and reactivity were not related to hormone levels in either group. This study indicates that asthmatics not previously aware of PMA will record a premenstrual worsening of asthma symptoms and peak expiratory flow rates. These changes are not related to a deterioration in spirometry and airway reactivity or to the absolute levels of circulating progesterone and estradiol.